List of cocaine analogues

This is a list of cocaine analogues. A cocaine analogue is a (usually) artificial construct of a novel chemical compound from (often the starting point of natural) cocaine's molecular structure, with the result product sufficiently similar to cocaine to display similarity in, but alteration to, its chemical function. Within the scope of analogous compounds created from the structure of cocaine, so named "cocaine analogues" retain 3β-benzoyloxy or similar functionality (the term specifically used usually distinguishes from phenyltropanes, but in the broad sense generally, as a category, includes them) on a tropane skeleton, as compared to other stimulants of the kind. Many of the semi-synthetic cocaine analogues proper which have been made & studied have consisted of among the nine following classes of compounds:[lower-alpha 1]

  • stereoisomers of cocaine
  • 3β-phenyl ring substituted analogues
  • 2β-substituted analogues
  • N-modified analogues of cocaine
  • 3β-carbamoyl analogues
  • 3β-alkyl-3-benzyl tropanes
  • 6/7-substituted cocaines
  • 6-alkyl-3-benzyl tropanes
  • piperidine homologues of cocaine
Above: Cocaine in the chair conformation of the tropane-ring, with only its tropane locants given.

Below: Alternate two-dimensional molecular diagram of cocaine; shown specifically as a protonated, NH+, hydrochloride, and disregarding 3D stereochemistry
Cocaine with its numerical substitution position locants.
2′ (6′) = ortho, 3′ (5′) = meta & 4′ = para

However strict analogues of cocaine would also include such other potential combinations as phenacyltropanes & other carbon branched replacements not listed above. The term may also be loosely used to refer to drugs manufactured from cocaine or having their basis as a total synthesis of cocaine, but modified to alter their effect & QSAR. These include both intracellular sodium channel blocker anaesthetics and stimulant dopamine reuptake inhibitor ligands (such as certain, namely tropane-bridged-excised, piperidines). Additionally, researchers have supported combinatorial approaches for taking the most promising analogues currently elucidated and mixing them to the end of discovering novel & efficacious compounds to optimize their utilization for differing distinct specified purposes.[lower-alpha 2]

Two dimensional schematic drawing of cocaine's structural dynamic interaction points with dopamine transporter binding sites.

Although the carbmethoxy is denoted in its function as a hydrogen bond in this depiction, it has been found that it is primarily electrostatic factors which dominate binding within this space of the molecular surface area over the operative principle of hydrogen bonding.[lower-alpha 3]
Two out of three potential "reverse esters" of cocaine (the third one being a single "di-substituted" structure with both the 'methyl ester' & 'benzoate' reversed in tandem)

Analogs sensu stricto

Cocaine Stereoisomers

There are eight stereoisomers of cocaine (with the internal portion of the tropane ring unchanged).[lower-alpha 4] Not counting mesomers but including the one & five to eight position bond bridge of the tropane system having R- & S- configurations potentially, containing four asymmetric carbons, cocaine can be counted as having as many as sixteen stereoisomers. However geometric constraints imparted by the bridgehead amine allow only eight to be created.
Stereoisomer S. Singh's
alphanumeric
assignation
IC50 (nM)
[3H]WIN 3542 inhibition to
rat striatal membranes
Mean error standard ≤5% in all cases
IUPAC
nomenclature
R-cocaine
(Erythroxyline)
102 methyl(1R,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-pseudococaine
(Delcaine, Depsococaine, Dextrocaine, Isococaine, Psicaine.[2])
172 15800 methyl(1R,2S,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allococaine 173 6160 methyl(1R,2R,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
R-allopseudococaine 174 28500 methyl(1R,2S,3R,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
S-cocaine 175 15800 methyl(1S,3R,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-pseudococaine 176 22500 methyl(1S,3R,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allococaine 177 9820 methyl(1S,3S,4R,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate
S-allopseudococaine 178 67700 methyl(1S,3S,4S,5R)-3-(benzoyl)oxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylate

Where the 2D diagrams given for the structural analogs below do not indicate stereochemistry, it should be assumed they share the conformation of R-cocaine, unless noted otherwise.

The natural isomerism of cocaine is unstable in several ways besides having a high degree of lability; for instance: the C2 carbomethoxy in its biosynthesis end-product maintains the axial position, which can undergo epimerization via saponification to obtain the former in an equatorial position.

The creation of the following analogues of cocaine have traditionally required a step which has utilized 2-CMT as an intermediate molecular product.

Benzoyl branch cleavage substitutions (excluding the exhaustive phenyl group)

Salicylmethylecgonine[3]Methylvanillylecgonine[4]

N.B. Fries rearrangement product of aspirin used to make salbutamol. It is relevant to the precursor here though because the migrated acetyl group can be the subject of a haloform reaction. A more direct route to vanillic acid though is just oxidation of the vanillin to a functionalized benzoic acid.

para-substituted benzoylmethylecgonines


Carbon 4′-hydrogen Substitutions (benzene-4′ "para" substituted benzoyloxytropanes)[lower-alpha 5]
Data-set congruent to, and aggregate with, following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
4′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

(cocaine)H249 ± 37615 ± 1202500 ± 702.510.0
non-benzoyloxy analogue
comparative ligands

non-tropane analogue
comparative ligands
11b (WIN 35428)
(nisoxetine)
(fluoxetine)
F

24 ± 4
775 ± 20
5200 ± 1270
690 ± 14
762 ± 90
15 ± 3
258 ± 40
135 ± 21
963 ± 158
28.7
1.0
0.003
10.7
0.2
0.2
183aI2522 ± 41052 ± 2318458 ± 10730.47.3
183bPh486 ± 63----
183cOAc144 ± 2----
183dOH158 ± 83104 ± 148601 ± 1119.63.8
(4′-Fluorococaine)[5]F-----
(para-Isothiocyanatobenzoylecgonine
methyl ester
)[6]
(p-Isococ)
NCS-----

The MAT binding pocket analogous to the lipophilic place on cocaine-like compounds, inclusive of the benzene ring, is approximate to 9 Å in length. Which is only slightly larger than a phenyl ring by itself.[lower-alpha 6]

meta-substituted benzoylmethylecgonines

Carbon 3′-hydrogen Substitutions (benzene-3′ "meta" substituted benzoyloxytropanes)[lower-alpha 7]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
3′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

184aI325ɑ----
184bOH1183 ± 115793 ± 333760 ± 5890.73.2
191OBn-----
(m-Isococ)NCS-----
  • ɑIC50 value for displacement of [3H]cocaine

ortho-substituted benzoylmethylecgonines

The hydroxylated 2′-OH analogue exhibited a tenfold increase in potency over cocaine.[lower-alpha 8]

Carbon 2′-hydrogen Substitutions (benzene-2′ "ortho" substituted benzoyloxytropanes)[lower-alpha 9]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
2′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

185aI350ɑ----
185bF604 ± 671770 ± 3091392 ± 1732.92.3
185c
(2′-Acetoxycocaine)[7]
OAc70 ± 1219 ± 2072 ± 93.11.0
185d
(2′-Hydroxycocaine)[3]
OH25 ± 4143 ± 2148 ± 25.71.9
  • ɑIC50 value for displacement of [3H]cocaine

manifold benzoyloxy phenyl-substitutions

Multi-substitutions (substitutions of substitutions; e.g. meta- & para-) or manifold ("many-fold") substituted analogues are analogues where more than one modification from the parent molecule takes place (having numerous intermediary constituents). These are created with often surprising structure–activity relationship results extrapolated therefrom. It is even a common case where two separate substitutions can each yield a weaker, lower affinity or even wholly non-efficacious compound respectively; but due to findings that oftentimes, when used together, such two mutually inferior changes being added in tandem to one analogue has the potential to make the resultant derivative display much greater efficacy, affinity, selectivity &/or strength than even the parent compound; which otherwise was compromised by either of those two alternations when made alone.

For an exposition & allusion to this mechanism observe that the opioid oxycodone, derived from codeine, is 1.5×—1.7× the analgesic potency of morphine (an opioid to which codeine is by comparison only 8%—12% as potent relatively, or 0.17th its strength in rats); yet oxycodone's intermediates in its synthesis from codeine are: ⅓ the potency of codeine (i.e. codeinone); 0.13 that of morphine (i.e. 14-hydroxycodeine) in rats and less in mice (to illustrate: the former even being less than the 0.17 of morphine that codeine is); with the final possible stand alone intermediate compound between codeine & oxycodone (i.e. 7,8-dihydrocodeine) being at most 150% to 200% that of codeine.[8]

Manifold Compositions of Terminating Phenyl Ring Substitutions (Multiple benzene-2′,3′ & 4′ combined substituted benzoyloxytropanes)[lower-alpha 10]
Data-set (excepting instanced references inside table) congruent to, and aggregate with, preceding and following tables
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
ortho-2′=R meta-3′=R para-4′=R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

186HOHI215 ± 19195 ± 101021 ± 750.94.7
(Vanillylmethylecgonine)[4]HOCH3OH-----

benzoyl phenyl-alterations

The naphthalene analogs allow for further numeric substitutions, including eight position peri substituted patterns. Many more alterations creating differing aromatic rings are possible.

Terminating Phenyl Carbon Ring Fusions & Alterations[lower-alpha 11]
Data-set congruent to, and aggregate with, preceding table
IC50 values
Structure S. Singh's
alphanumeric
assignation
(name)
C=R DAT

[3H]Cocaine (IC50)

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

1871-naphthalene742 ± 48----
1882-naphthalene327 ± 63----

Benzoyl branch modifications

Spirocyclic benzoyl branch modification that fits criteria as a cocaine analog and a phenyltropane both (tropane 2nd locant ester rendered in given depiction shows, as has been attested, to only having been successfully alpha configured)[9]


A sulfur in place of the oxygen at the benzoyl ester single bond results in a lower electronegativity than that of cocaine.

C1-tropane-ring hydrogen—substitutions


cf. hydroxytropacocaine for a natural alkaloid (lacking however, the 2-position carbmethoxy) that is a C1 substituent with a hydroxy group.

C1 substitutions[11]
HEK-293 heterologously expressed human monoamine transporter cells for Ki values of compounds inhibiting neurotransmitter uptake.[12]
Structure Trivial name R
(C1 moiety)
Ki (nM) @ DAT Ki (nM) @ SERT Ki (nM) @ NET σ1 affinity
Ki
σ2 affinity
Ki
IC50 (μM) Na+ inhibition
(Vertridine-Stimulated
influx of sodium channels
in Neocortical neurons)c
LogP
(XLogP3 algorithm, Cheng et al., 2007)
(—)-CocaineH326 ± 106513 ± 143358 ± 696.7 ± 0.3 μMd[13]"significant"[14]6.99 ± 2.432.30
(—)-1-methyl-cocaineMe163 ± 23435 ± 77488 ± 101"unappreciable"1.13 μM16.01 ± 1.902.67
(—)-1-ethyl-cocaineEt95.1 ± 17.0ɑ1,106 ± 112598 ± 1793.20
(—)-1-n-propyl-cocainen-Pr871 ± 205ɑ2,949 ± 462b796 ± 1953.56
(—)-1-n-pentyl-cocainen-C5H111,272 ± 199b1,866 ± 400ɑ1,596 ± 21b4.64
(—)-1-phenyl-cocainePh32.3 ± 5.7b974 ± 3081,980 ± 99b524 nM198 nM0.29 ± 0.073.77
  • ɑ, P < 0.05 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
  • b, P < 0.01 compared with (—)-cocaine (one-way ANOVA followed by Dunnett's multiple comparisons test)
  • cLidocaine was found to have a value of 39.6 ± 2.4, the weakest of all tested.
  • dSame reference gives 25.9 ± 2.4 μM for (+)-cocaine and 13.6 ± 1.3 μM for norcocaine. Comparably it gives 12.7 ± 1.5 μM for the sigmaergic affinity of (+)-amphetamine. Another reference gives 1.7-6.7 μM for (—)-cocaine. All values Ki.[15]
  • Using same data-set as above table, the following compounds were found to compare as:
    • CFT @ DAT = 39.2 ± 7.1 (n = 5)
    • fluoxetine @ SERT = 27.3 ± 9.2 (n = 3)
    • desipramine @ NET = 2.74 ± 0.59 (n = 3)

Cocaine analogs substituting the C1-tropane ring position, requiring sulfinimine (N-sulfinyl-imine) chemistry (before the innovation of which were untenable) which bind unlike the typical configuration at DAT (open to out) as cocaine (with its terminal D79-Y156 distance of 6.03 Å), or in the atypical (closed to out) conformation of the benztropines (3.29 Å). Though closer to the open to out: (—)-1-methyl-cocaine = 4.40 Å & (—)-1-phenyl-cocaine = 4.89 Å, and exhibiting preferential interaction with outward facing DAT conformation, they appear to have the lack of behavioral stimulation as-like the closed to out type. Despite having non-stimulant behavior profiles, they still seem to have anti-depressant behavioral profiles.[12]

The C1 phenyl analog is ten times stronger than cocaine as a dopamine reuptake pump ligand, and twenty four times stronger as a local anesthetic (voltage-dependent Na+ channel blocker), whereas the C1 methyl analog is 2.3 times less potent as a local anesthetic.[12]

2β-substitutions (including transesterification metabolite substitution cocaethylene)

Extra methylene length to the 196c cocaine analogue, as given in error previously; "2-methylpropyl", i.e. isobutanol.


The consideration that large, bulky C2 substituents would alter the tropane by distorting the piperidine ring part of its skeleton sufficiently enough to impair its functionality, or that in said event such would hamper binding, in particular at the 8-aza end to ease steric strain going toward its place from the 2-position,[lower-alpha 12] appear to in many cases be unfounded.[lower-alpha 13] (examples shown in table of images below)

Compounds with greater SERT affinity than cocaine parent (slightly less @ DAT, significantly less, except for #196g, @ NET)

Compounds with greater DAT affinity than cocaine parent (SERT & NET affinity untested; note however their similarity to more potent SERT ligands above) (greater)>@ DAT, (lesser)<@ SERT, (much less)<<@ NET
hydroxypropylbenzoylecgonine (HPBE), which imparts the topical analgesic effect in the preparation Esterom.[16]

Compound 197b displayed a 1,131-fold increased selectivity in affinity over the serotonin transporter, with only slight reductions in potency for the dopamine & norepinephrine transporters.[lower-alpha 14] Whereas 197c had a 469× increase at SERT, with greater affinity for DAT than cocaine & was approximately equipotent to NET.[lower-alpha 15] 197b was 137×, and 196c 27× less potent at binding to the serotonin transporter, but both had a NET / DAT ratio that made for a better dopaminergic than cocaine.[lower-alpha 16]

Direct 2β Substitutions[lower-alpha 17]
(IC50 nM values)
Structure S. Singh's
alphanumeric
assignation
(name)
R DAT

[3H]WIN 35428

5-HTT

[3H]Paroxetine

NET

[3H]Nisoxetine

Selectivity

5-HTT/DAT

Selectivity

NET/DAT

(Cocaine)Me89 ± 4.81045 ± 893298 ± 29311.737.0
196a
(Cocaethylene)
Et195 ± 455801 ± 49310000 ± 75129.751.3
196bn-Pr196 ± 464517 ± 4306124 ± 26223.331.2
196ci-Pr219 ± 4825224 ± 149830384 ± 1685115139
196dPh112 ± 3133666 ± 333031024 ± 1909300277
196eBn257 ± 14302 ± 2320794 ± 9501.280.9
196fβ-phenethyl181 ± 10615 ± 5219944 ± 10263.4110
196gγ-phenylpropyl147 ± 19374 ± 154893 ± 3442.533.3
196hcinnamyl371 ± 15368 ± 6.368931 ± 34761.0186
196ip-NO2-β-phenethyl601 ± 28----
196jp-Cl-β-phenethyl271 ± 12----
196kp-NH2-β-phenethyl72 ± 7----
196lp-NCS-β-phenethyl196 ± 14----
196mp-azido-β-phenethyl227 ± 19----
196n(p-NHCOCH2Br)β-phenethyl61 ± 6----
196o(p-NHCO(CH2)2CO2Et)β-phenethyl86 ± 4----
197aNH2753 ± 41.313725 ± 12563981 ± 22918.25.3
197b-NMe2127 ± 6.36143713 ± 88547329 ± 158113157.7
197c-N(OMe)Me60 ± 6.428162 ± 25653935 ± 26646965.6
197d-NHMe2424 ± 11844798 ± 21054213 ± 20618.51.7
197e
(Benzoylecgonine)
-OH195000----
197fHOCH2-561 ± 149----
197g
(Tropacocaine)
H5180 ± 1160----

Bioisostere 2-position carbmethoxy-ester functional replacements

Intermediate compound #203


Benzoylecgonine, i.e. compound 197e, (differing from its cocaine parent only by de-methylation of the C2 carbmethoxy to that of a carboxy) has an extreme loss in potency (its approximate affinity being 195,000 nM) as displayed by in vitro methodologies for determining binding efficacy (wherein BBB penetration does not factor-in on the matter in the manner as in vivo studies) and is posited to be due possibly to zwitterion formation.[lower-alpha 18]

2β-isoxazole and isoxazoline ring containing analogues[lower-alpha 19]
Data-set congruent to, and aggregate with, following tables
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
(name)
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

(Cocaine)(H)580 ± 70570 ± 1801.0
198aH520 ± 40260 ± 700.5
198bCO2Et (5′-carboethoxy-)120 ± 10290 ± 402.4
198cBOC2230 ± 2201820 ± 8100.8
198dPh2000 ± 6402920 ± 16201.5
198eCH=CHCO2Me3600 ± 4003590 ± 11801.0
2-[(2-methoxy-2-oxoethoxy)methyl] cocaine analogue.[17]

[2H3-N-methyl]-cocaine: reagent analogue used in radio-labeling ligand binding sites.
nonplanar 2β-isoxazoline ring containing analogues[lower-alpha 20]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

199aβ(or R)CO2Et710 ± 1501060 ± 3401.5
199bα(or S)CO2Et5830 ± 6308460 ± 6201.4
C2-ethyl-OSO2CF2 cocaine analogue.[17]

2β-isoxazoline atomically N/O reversed analogues[lower-alpha 21]
Data-set congruent to, and aggregate with, preceding and following tables
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

200880 ± 350400 ± 1400.4

Vinylogous 2β-position carbmethoxy-ester functional replacements

201b & 201c show significant increased potency over cocaine; whereas 201a, 201d & 201e are considerably less so. This infers the hydrogen bond acceptor at the 2β position to not necessarily be of exclusive import in creation of higher binding analogues of cocaine.

[2H5-phenyl]-cocaine: reagent analogue, as above thumbnail of similar compound: rendered from its cocaine parent by replacing a cluster of several adjacent hydrogens (from among the hydrogens that comprise the entire circumference common to every basic molecular perimeter) with deuterium, in an equivalent but localized spread or cluster.
vinylogous 2β analogues[lower-alpha 22]
Data-set congruent to, and aggregate with, preceding table
IC50 nM values
Structure S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

201aH1730 ± 5501120 ± 3900.6
201bCl222 ± 49368 ± 1901.6
201cCO2Et50 ± 10130 ± 102.6
201dCH=CHCO2Et1220 ± 100870 ± 500.7
201ePO(OEt)24850 ± 4705500 ± 701.1

N-modifications

Additional N-modified cocaine analogue molecular structures


8-oxa cocaine analogs:[18] (cf Meltzer with PTs)
Eight position carba N6 & N7 analogues.[17]
ortho-phenyl of the moved nitrogen.[17]
Nitrogen Substitutions
Mazindol comparison table
(ɑβ-CFT comparison notation)[lower-alpha 23]
Compound S. Singh's
alphanumeric
assignation
(name)
N8-R [3H]Mazindol
binding
[3H]DA
uptake
Selectivity

Uptake/Binding

217
(Cocaine methiodide)
-10700 ± 1530ɑ--
(Cocaine)CH3280 ± 60
102ɑ
320 ± 101.1
218
(Norcocaine)
H303 ± 59ɑ--
219aBn668 ± 67ɑ--
219bAc3370 ± 1080ɑ--
219cCH2CH2OH700 ± 1001600 ± 2002.3
219dCH2CO2CH3480 ± 401600 ± 1003.3
219eCH2CO2H380 ± 202100 ± 4005.5
220aSO2CH3 (Ms)1290 ± 801970 ± 701.5
220bSO2CF3 (Tf)330 ± 30760 ± 202.3
220cSO2NCO120 ± 10160 ± 101.3
220dSO2Ph20800 ± 3500610002.9
220eSO2C6H4-4-NO2 (nosyl)5720 ± 114018800 ± 903.3
220fSO2C6H4-4-OCH36820 ± 58016400 ± 14002.4
221aNO99500 ± 12300231700 ± 395002.3
221bNO27500 ± 90021200 ± 6002.8
221cNHCOCH3>1000000>1000000-
221dNH2---
  • ɑIC50 (nM) for displacement of [3H]WIN 35428

8 to 2 position tropane bridge

A selection of "front bridged" & "back bridged" cocaine analogs.
See N-front & back bridged phenyltropanes.
Derivations upon fusions of the tropane's nitrogen bridge[lower-alpha 24]
Compound S. Singh's
alphanumeric
assignation
R [3H]Mazindol [3H]DA Selectivity

Uptake/Binding

22244900 ± 6200115000 ± 157002.6

Back-bridged cocaine analogues are considered more akin to untethered cocaine analogs & phenyltropane derivatives (where the nitrogen lone pair is not fixed or constrained) and better mimics their affinities. This is due to when the eighth carbon tropane position is freely rotatable and unbound it preferably occupies the axial position as defining its least energy & most unhindered state. In front-bridged analogs the nitrogen lone pairings rigid fixity makes it reside in an equatorial placing for the piperidine ring-part of the tropane nucleus, pointing to the two-carbon & three methylene unit bridgehead; giving the attested front-bridged cocaine analogues preference for SERT over DAT.[lower-alpha 25]

Tricyclic cocaine analogues

Tethering the nitrogen 8 tropane position one position further (beyond 2β and crossed-over it / leaving it open as hydrogen and thus possible of having additional unconstrained substitutions there) and linking all the way across to the 3β aryl, replacing it; yields an expansive front-bridged structure to create a structurally tricyclic series of cocaine analogues.

8 to 3 position

Constrained thiophene tropane[19][20] Note the pi symmetry of the partially hydrogen-unsaturated cyclopentane substitutes the benzene place with the other tricyclic tropanes to the left.
Tricyclic tropanes, values in Ki (nM)[21]
1st structure (di-chloro benzene, 2β-CH2OCOMe) SERT = 1.6, DAT = 1870, NET = 638
2nd structure (para-bromo, meta-chloro, 2β-CO2Me) SERT = 2.3, DAT = 5420, NET = 459
3rd structure (para-iodo, meta-chloro, 2β-CH2OCOPh) SERT = 0.06, DAT/NET both = >10K
CompoundXYRSERT Ki (nM)DAT Ki (nM)NET Ki (nM)
1ClClCH2OCOMe1.61870638
2BrClCO2Me2.35420459
3IClCH2OCOPh0.06>10K>10K

Azabornane tropane ring contraction

Alterations shortening the tropane ring system while including the benzoyloxy length at the C3 have been made, contrasting the azabornane phenyltropanes;[17] likely remedying the shallow penetration (for good efficacy) of the latter.
5-benzoatic (left, below) & 6-benzoatic (right, below)


Comparison of tropane ring versus the norbornane in overlay, with contrast of benzoyl branch in its configuration of how it lays extended out from body of either main ring type (shown twice in different colors, for visibility, above)

6/7 tropane position methoxycocaine & methoxypseudococaine analogues

Phenylsulfanyl, C2-C3 unsaturated nonisomeric (C2 inclusive) C4 chloro analog.[17]
Substitutions upon the 6 & 7 positions of the tropane[lower-alpha 26]
Compound S. Singh's
alphanumeric
assignation
(name)
X Ki (nM)
[3H]Mazindol binding
Ki (nM)
[3H]DA uptake
Selectivity

Uptake/Binding

(Cocaine)280 ± 60320 ± 101.1
(Pseudococaine)10400 ± 30013800 ± 15001.3
225a2β, 6β-OCH398000 ± 1200068000 ± 50000.7
225b2α, 6β-OCH3190000 ± 11000510000 ± 1100002.7
225c2β, 7β-OCH34200 ± 1006100 ± 2001.4
225d2α, 7β-OCH345000 ± 5000110000 ± 40002.4
225e2α, 7α-OCH354000 ± 3000200000 ± 700003.7

3β-position 2′—(6′) & 2β-substitution combination analogues


4′-Iodococaine-2β-substituted analogues[lower-alpha 27]
Compound S. Singh's
alphanumeric
assignation
2β-R C2′-R IC50 (nM)
(displacement of [3H]WIN 35428)
211aCO2OHH6214 ± 1269
211bCH2OCOCH3H2995 ± 223
211cCONHCH3H>100000
211dCO2EtH2031 ± 190
211eCO2-i-PrH1377 ± 10
211fCO2PhH2019 ± 253
211gCO2CH2PhH4602 ± 325
211h3-phenyl-1,2,4-oxadiazoleH3459 ± 60
211iCH=CH2H2165 ± 253
211jCH2CH3H2692 ± 486
212CO2-i-PrHO663 ± 70
4507 ± 13ɑ
34838 ± 796b
  • ɑFor displacement of [3H]paroxetine (5-HTT & NET)
  • bFor displacement of [3H]nisoxetine (5-HTT & NET)

3β-Carbamoyl analogues



3-position carbamoyl linkage substituting benzoyloxy analogues[lower-alpha 28]
Compound S. Singh's
alphanumeric
assignation
(name)
X IC50 (nM)
inhibition of [3H]Cocaine binding
(Rat Striatal Tissue)
IC50 (nM)
inhibition of [3H]DA uptake
(Rat Striatal Tissue)
Selectivity
uptake/binding
(Cocaine)(H)70 ± 10210 ± 703.0
223aH5600 ± 70052600 ± 30009.4
223b4-NO21090 ± 2505700 ± 12005.2
223c4-NH263300 ± 12200>100000-
223d4-N31000 ± 2401180 ± 3601.2
223e4-NCS260 ± 60490 ± 801.9
223f3-NO237 ± 10178 ± 234.8
223g3-NH22070 ± 34023100 ± 90011.1
223h3-N3630 ± 1503900 ± 15906.2
223i3-NCS960 ± 2104900 ± 4205.1

Phenyl 3-position linkage substitutions

A 3-Dimensional (stick-&-ball) rendering of Troparil: A structural analogue of cocaine with omitted -COO- linkage – a parent compound of many MAT ligands; those of the phenyltropane class. (Here it is depicted in an unfavourable conformation of the O-Me; The methyl has to be at the other oxygen and trans to optimize its functional stimulation.)
The top image above is a 2-Dimensional emulation of the orientation for the animated 3D image to the far right, with a methoxy that is distal from the phenyl group and cis. While the alternate image below that to its bottom shown above is one with the carboxyl methyl group proximal to the phenyl, in its optimum conformation, with a likewise optimum trans configuration.

See: List of phenyltropanes (Many phenyltropanes are derived from cocaine metabolites, such as methylecgonidine, as precursors. Whereas fully synthetic methods have been devised from the starting material of vinylcarbenoids & pyrroles.)[22]

The difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.[lower-alpha 29] This may account for PTs increased behavioral stimulation profile over cocaine.[lower-alpha 30] Differences in binding potency have also been explained considering solvation effects; cocaine containing 2β,3β-ester groups being calculated as more solvated than the WIN-type compounds (i.e. troparil). Higher pKɑs of the tropane nitrogen (8.65 for cocaine, 9.55 for troparil & 11.95 for vinyl analogue 43a), decreased aqueous solvation & decreased conformational flexibility added to increased binding affinity.[lower-alpha 31]

Despite the observation of increased stimulation, phenyltropanes lack the local anesthetic sodium channel blocking effect that the benzoyloxy imparts to cocaine. Beside topical affect, this gives cocaine an affinity for binding to sites on the dopamine and serotonin sodium dependent transport areas that are distinct & specific to MAT in contrast to the general sodium channels; creating a separate mechanism of relational affinity to the transporters in addition to its inhibition of the reuptake for those transporters; this is unique to the local anesthetic value in cocaine & analogues with a similar substitute for the benzoyloxy that leaves the sodium channel blockage ability intact. Rendering such compounds as different functionally in their relation to MAT contrasted to phenyltropane analogues which have the local anesthetic bridge removed.[23] (Requiring some of the sodium ions to be pumped from the axon via Na+/K+-ATPase). In addition, it even has been postulated that a crucial role regarding the electron energy imparted via voltage sensitization (and thus action potential blockage with a molecule capable of intersecting its specific channel, in the case of cocaine a sodium channel, that potentially serves in re-quantifying its charge) upon a receptor binding site may attenuate the mediating influence of the inhibitory regulation that autoreceptors play by their slowing neurotransmitter release when an efflux is created through an instance of agonism by a compound; allowing said efflux to be continued without the body's attempt to maintain homeostasis enacting in as readily responsive a manner to its conformational change.[24]

Various phenyltropane examples


3β-Alkylphenyltropane & 3β-Alkenyl analogues

The compound 224e, the 3β-styrene analogue, had the highest potency in its group. While 224b & 224c showed the most selectivity, with 224b having a ten-fold greater potency for the dopamine transporter than cocaine.[lower-alpha 32]


3β-styrene alkylphenyl cocaine analog image showing stereochemistry.
(i.e. compound "224e")
3-position alkylphenyl linkage substituting benzoyloxy analogues[lower-alpha 33]
Compound S. Singh's
alphanumeric
assignation
(name)
n IC50 (nM)
[3H]Cocaine binding
IC50 (nM)
[3H]DA uptake
Selectivity
uptake/binding
(Cocaine)101 ± 26209 ± 202.1
224a1885 ± 181020 ± 521.1
224b29.9 ± 0.3370.5 ± 1.07.1
224c3344 ± 122680 ± 1907.8
224d71.6 ± 0.7138 ± 91.9
224e2.10 ± 0.045.88 ± 0.092.8

6-Alkyl-3-benzyltropane analogues

Cocaine 229b—f series analogues


Cocaine 230b—f series analogues


Cocaine 231c—f series analogues


Cocaine 232c, d & f series analogues

6-Alkyl-3-benzyl-2[(methoxycarbonyl)methyl]tropane analogues[lower-alpha 34]
Compound S. Singh's
alphanumeric
assignation
(name/WIN number)
R Ki (nM)
[3H]WIN 35428 binding
IC50 (nM)
[3H]DA uptake
Selectivity

uptake/binding

(Cocaine)32 ± 5
338 ± 221
405 ± 91
405 ± 91
12.6
1.2
11a
(WIN 35065-2)
33 ± 17
314 ± 222
373 ± 1011.3
(−)-229aH33 ± 5161 ± 1004.9
229aH91 ± 1094 ± 261.0
229bMe211 ± 23--
229cEt307 ± 28--
229dn-Pr4180 ± 418--
229en-Bu8580 ± 249--
229fBn3080 ± 277--
(+)-230aH60 ± 6208 ± 633.5
230aH108 ± 14457 ± 1044.2
230bMe561 ± 64--
230cEt1150 ± 135--
230dn-Pr7240 ± 376--
230en-Bu19700 ± 350--
230fBn7590 ± 53--
231bMe57 ± 5107 ± 361.9
231cEt3110 ± 187--
231dn-Pr5850 ± 702--
231fBn1560 ± 63--
232bMe294 ± 29532 ± 1361.8
232cEt6210 ± 435--
232dn-Pr57300 ± 3440--
232fBn3080 ± 277--
241Bn4830 ± 434--
Benzylidene derivatives of 6-alkyl-3-benzyltropanes[lower-alpha 35]
Sub-category
(S. Singh compound #)
a
R=H
b
R=Me
c
R=Et
d
R=n-Pr
e
R=n-Bu
f
R=Bn
6α-isomers:
237a—f
6β-isomers (exo):
238a—f

3β-benzyl derivatives:
239a—f
intermediate
alkylidene esters:
240a—f

N.B. that 237a and 238a are the same compound as both are the parent for either series with a hydrogen saturated in their respective substitution place.

Direct 2,3-pyrimidino fused

above: Strobamine, a DARI functional cocaine analog with structural semblance.[25] Compare the phenyltropane length tropane C2 & C3 functional group fusion variant.[26]

below: Chalcostrobamine

cf. strobamine (at right) for a more efficacious compound as like the below.

2,3-direct fused "di-hetero-benzene" rigidified cocaine analogs.[27]
(Binding values @ biogenic amine transporters (BATs) for rigid and semi-rigid analogs)
Structure alphanumeric
assignation
R1 R2 hDAT
IC50 (nM)
hSERT
IC50 (nM)
hNET
IC50 (nM)
(—)-3aHC6H558,300 (20,200)6140 (3350)NA
(+)-3aHC6H548,700 (20,100)6030 (3400)NA
(—)-3bHNH2NANANA
(+)-3bHNH2NANANA
(—)-3cHCH3NANANA
(+)-3cHCH3NANANA
(—)-3dHHNANANA
(+)-3dHHNANANA
(+/—)-3eC6H5C6H530,000 (11,200)3650 (1700)NA
  • "NA" = "no affinity", e.g. unquantifiable.

Direct di-hetero-benzene (pyrimidino) 2,3-fused and thus rigidified cocaine analogs.[27]

Piperidine cocaine-homologues

Tricyclo benzoyloxy dibenzene cocaine analogue. cf. benztropine compound #277, tropatepine, etc.[17]

cf. phenyltropane piperidine-homologues for compounds with a more optimized conformation that yield higher affinities when binding to MAT.

binding potency of piperidine homologues for displacement of [3H]WIN 35428[lower-alpha 36]
Compound S. Singh's
alphanumeric
assignation
(name)
2β-R IC50 (nM)
(Cocaine)CO2CH3
(i.e. CO2Me)
249 ± 37
183aCO2CH32522 ± 4
242H11589 ± 4
243CO2CH38064 ± 4

Cocaine hapten analogues

"GNC", a cocaine analog designed to minimize the formation of noncocaine-like structures through its chemical coupling to the Ad proteins; all while maintaining the element of its antigenic determinant from the moiety of cocaine.[28]
Cocaine analogs which elicit noncatalytic antibodies[lower-alpha 37]
Compound S. Singh's
alphanumeric
assignation
(name)
2β-R
394
(GNC)ɑ
CO2(CH2)5CO2H
395
(Succinyl Norcocaine)[29]
CO2CH3
GNEb[30]
including carrier proteins:
GNE-FLiC
GNE-KLH
GNE-BSA
396CONH(CH2)5CO2H
  • ɑ6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carbonyloxy-hexanoic acid
  • b6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid
Tetrahedral-intermediate cocaine-hapten compound #400
Cocaine transition state analogues (TSAs) which generate catalytic antibodies[lower-alpha 38]
Compound S. Singh's
alphanumeric
assignation
(name)
R
401aCH3
401b(CH2)5CO2H
401cCH2CO2H
401dCOCH2CH2CO2H
401eH
401fCH2CH2Br
385g(CH2)2NHCO(CH2)2CONH2
402aO(CH2)4NHCO(CH2)2CO2...2,3-dihydro-1H-isoindole-1,3-dione
402bOH
402cO(CH2)2...1,4-xylene...NH2
402dNH(CH2)5CO2H
402eO(CH2)4NHCO(CH2)2CONH2
403aNH2
403bNHCOCH2Br
403cNHCO(CH2)3CO2H
403d(CH2)3NHCO(CH2)2CONH2

Cocaine haptens that create catalytic anti-bodies require transitional states as affected in vivo.[31][32]

Anti-idiotypic & butyl-cholinesterase mediated immunopharmacotherapy cocaine analogs[33]
Compound Name
K1-KLH/BSA[34]
K2-KLH/BSA

Structural/Functional intermediate analogues

Piperidine Analogues

A somewhat recent occurrence among tentative modern folklore which has traversed the circling of rumors mostly confined to the likes of universities and popular culture trivia has been that cocaine is one element, or molecule increment of weight or charge etc., away from the molecular structure of sugar.[36] Though such a statement is false as a general pretense, there is a dextrose based super-structure that has a vaguely similar overlay with cocaine which is "benzoyl-beta-D-glucoside."

Benztropine (3α-Diphenylmethoxy Tropane) Analogs

  • Benzatropine (BZT)[37]
  • Difluoropine (O-620), More selective as a DARI than cocaine. Also an anticholinergic & antihistamine.
  • AHN 1-055 Same structure as for benztropine but 4′,4′-bisfluorinated.
  • GA 103 N-phenylpropyl bis-4-fluorobenztropine.
  • JHW 007[38] N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane.


Unlike cocaine & phenyltropanes, the benztropines & GBR compounds (and, as an exception to the cocaine pharmacophore itself, allotropacocaine) among others are considered "atypical" DAT re-uptake pump ligands because they stabilize the dopamine transporter in an inward-facing or closed-to-out conformation, this contrasts what is considered "cocaine-like" affinity to DAT; which would instead keep DAT stable in an open-to-out conformation. This means the binding of many dopamine reuptake inhibitors is atypical of cocaine's method of binding to DAT and significantly diverges from it.[39]

"Difluoropine" is not a phenyltropane but actually belongs to the benzatropine family of DRIs. Not to be confused for the "diaryl"-phenyltropanes.

In certain respects these are important because they share SAR overlap with GBR 12909 and related analogs.

SARs have shown that 4′,4′-difluorination is an excellent way to boost DAT activity of benztropine, and gives excellent selectivity over the SERT and the NET.[40][41]

Furthermore, replacing the N-Me with, e.g. n-phenylpropyl helps to bring muscarinic activity down to something that is the same as DRI affinity.[40]

This is remarkable considering unmodified (native) benztropine is 60 times more active as an anticholinergic than as a dopaminergic.[40]

M1 receptor considerations aside, analogues of this benztropine class still won't substitute for cocaine, and have no propensity to elevate locomotor activity.

Compound 276
3-CPMT
PG01053
MFZ 2-71
MFZ 4-86
3α-Diphenylmethoxy tropanes
(Benztropine analog affinities binding to DAT & DA uptake)[lower-alpha 39]
Compound S. Singh's
alphanumeric
assignation
(name)
R R′ Ki (nM)
[3H]WIN 35428 binding
IC50 (nM)
[3H]DA

uptake

Selectivity

uptake/binding

(Cocaine)388 ± 47--
(GBR 12909)11.6 ± 31--
(Benztropine)HH118 ± 9403 ± 1153.4
249a4′-FH32.2 ± 10481.5
249b
(AHN 1-055)
4′-F4′-F11.8 ± 1716.0
249c3′,4′-di-FH27.9 ± 11181 ± 45.76.5
249d4′-ClH30.0 ± 121153.8
249e4′-Cl4′-Cl20.0 ± 14753.8
249f3′,4′-di-ClH21.1 ± 19472.2
249g3′,4′-di-ClF18.9 ± 14241.3
249h4′-BrH37.9 ± 7290.8
249i4′-Br4′-Br91.6340.4
249j4′-NO2H197 ± 82191.1
249k4′-CNH196 ± 92221.1
249l4′-CF3H635 ± 1021553.4
249m4′-OHH297 ± 136772.3
249n4′-OMeH78.4 ± 84686.0
249o4′-OMe4′-OMe2000 ± 728761.4
249p4′-MeH187 ± 55122.7
249q4′-Me4′-Me420 ± 725366.0
249r4′-EtH520 ± 89841.9
249s4′-t-BuH191844562.3
250a3′-FH68.5 ± 12250 ± 64.73.6
250b3′-F3′-F47.4 ± 1407 ± 63.98.6
250c3′-ClH21.6 ± 7228 ± 77.110.5
250d3′-CF3H187 ± 5457 ± 72.02.4
251a2′-FH50.0 ± 12140 ± 17.22.8
251b2′-ClH228 ± 9997 ± 1094.4
251c2′-MeH309 ± 61200 ± 1.643.9
251d2′-NH2H840 ± 8373 ± 1170.4
3α-Diphenylmethoxy-2β-carbomethoxybenztropine
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)[lower-alpha 40]
Compound S. Singh's
alphanumeric
assignation
(name)
R R′ IC50 (nM)
DAT
(Binding of [3H]WIN 35428)
IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
Selectivity
5-HTT/DAT
(benztropine)312 ± 1.124100 ± 1480077.2
(WIN 35428)12.9 ± 1.1160 ± 2012.4
R-2562040 ± 2831460 ± 2550.7
S-257aHH33.5 ± 4.510100 ± 1740301
S-257bHF13.2 ± 1.94930 ± 1200373
S-257c
(difluoropine)
FF10.9 ± 1.23530 ± 1480324
S-257dHCl15.8 ± 0.955960 ± 467377
S-257eClCl91.4 ± 0.853360 ± 148036.8
S-257fHBr24.0 ± 4.65770 ± 493240
S-257gBrBr72.0 ± 3.652430 ± 33933.7
S-257hHI55.9 ± 10.39280 ± 1640166
S-257iBrI389 ± 29.44930 ± 8212.7
S-257jII909 ± 798550 ± 4429.4
S-257kHMe49.5 ± 6.013200266
S-257lMeMe240 ± 18.49800 ± 268040.8
Compound 277
N-Modified 2-carbomethoxybenztropines
(Benztropine affinities to DAT & 5-HTT in cynomologous monkey caudate-putamen)[lower-alpha 41]
Compound S. Singh's
alphanumeric
assignation
(name)
R n IC50 (nM)
DAT
(Binding of [3H]WIN 35428)
IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
Selectivity
5-HTT/DAT
258a20.3 ± 3.5--
258bH1223 ± 534970 ± 70022.3
258cH322.0 ± 11.919.7 ± 30.9
258dBr380.2 ± 8.8234 ± 0.52.9
258eI3119 ± 112200 ± 125018.5
258fH599.0 ± 28550 ± 635.5
259616 ± 8855200 ± 2000089.3
N-substituted 3α[bis(4′-fluorophenyl)methoxy]tropanes
(Benztropine affinities to DAT & 5-HTT)[lower-alpha 42]
Compound S. Singh's
alphanumeric
assignation
(name)
R Ki (nM)
DAT
(Binding of [3H]WIN 35428)
IC50 (nM)
5-HTT
(Uptake of [3H]DA)
Selectivity
uptake/binding
260
(AHN 2-003)
H11.2 ± 119.70.9
261a3-phenylpropyl41.9 ± 112305.5
261bindole-3-ethyl44.6 ± 11120026.9
261c4-phenylbutyl8.51 ± 14394.6
261d4-(4′-nitrophenyl)butyl20.2 ± 1165032.2
261e3-(4′-fluorophenyl)propyl60.7 ± 12--
262an-butyl24.6 ± 837015.0
262bcyclopropylmethyl32.4 ± 91805.5
262callyl29.9 ± 10140.5
262dbenzyl82.2 ± 152903.5
262e4-fluorobenzyl95.6 ± 102002.1
262fcinnanyl86.4 ± 121802.1
262g[bis(4-fluorophenyl)methoxy]ethyl634 ± 23--
262h[(4-nitrophenyl)phenylmethoxy]ethyl57.0 ± 17--
263acetyl234046002.0
264formyl2020 ± 1354002.7
265aTs0%ɑ--
265bMs18%ɑ--
(AHN 2-005)[42]CH2CH=CH2---
(JHW 007)[42]CH2CH2CH2CH3---
(GA 2-99)[42]CH2CH2NH2---
(GA 103)[42]CH2CH2CH2CH2Ph---
266108 ± 121301.2

ɑInhibition at 10 μM

Deuterium labeled radio-ligand of benztropine analog JHW-007; a di-para-fluoro benztropine, and hybrid between benzatropine & difluoropine (with fluorine groups in the former to breach the difference or the latter being descarbmethoxy to approach identification with the former).
8-Oxa-2-carbomethoxy norbenztropines
(8-Oxanortropane benztropine analog affinities to DAT & 5-HTT)[lower-alpha 43]
Compound S. Singh's
alphanumeric
assignation
(name)
IC50 (nM)
DAT
(Binding of [3H]WIN 35428)
IC50 (nM)
5-HTT
(Binding of [3H]Citalopram)
R/S-2682β,3β>10000>1660
R/S-2692α,3β20300>1660
R/S-2702α,3α22300>1660
R/S-2712β,3α520>1660

Tropanyl Isoxazoline Analogues

Spirocyclic tropanyl-Δ(2)-isoxazoline compound:
3′-methoxy-8-methyl-spiro(8-azabicyclo(3.2.1)octane-3,5′(4′H)-isoxazole which allosterically enhances SERT binding of other reuptake ligands. Compound 7a (likewise compound 11a with regard to DAT), construed as a potentiating allosteric effect (by unveiling occluded configured serotonin uptake-area ligand-site on surface of transporter that allows for binding by exogenous ligand, when SERT is otherwise conformed in a transitional manner where a SERT ligand cannot bind, this effect with compound in question occurs) at concentrations of 10μM—30μM (wherein it acts by interconverting the conformational state of unexposed SERTs to ones exposing the SSRI binding site via a shift to the equilibrium of the MAT) while exerting an inhibitory orthosteric effect when concentrations reach >30μM and above.

This is the only known compound to allosterically modulate SERT in such a way within in vitro conditions (tianeptine has been shown to do similar, but has only shown efficacy doing so in living in vivo tissue samples). Considering its noncompetitive inhibition of 5-HT transporters decreasing Vmax with small change in the Km for serotonin, putatively stabilizing the cytoplasm-facing conformation of SERT: in such respect it is considered to have the opposite effect profile of the anti-addiction drug ibogaine (save for the function by which its anti-addictive properties are thought to be mediated, i.e. α3β4 nicotinic channel blockage. cf. 18-Methoxycornaridine for such nicotinergic activity without the likewise SERT affinity).[43]

Similarly, such peripheral DAT considerations (when, as often is, considered conformational rather than otherwise explained as being electrostatic) may constitute the difference in affinity, through allosertic occulsion, between cyclopentyl-ruthenium phenyltropane in its difference from the tricarbonyl-chromium
Tropanyl-Δ2-isoxazoline derivatives[44]
Compound Name
-
4a4c5a5c
-
6a6b6c7a
-
7b7c8a8b
-
8c9a9b9c
-
9c10a10b10c
-
11a11b12a12b

8-Aminopentacyclo (σ receptor ligand) Trishomocubane Analogs

cf. other trishomocubanes such as basketane.

Sigma receptor agonists with nanomolar affinity such as CM156 have been shown to counteract the deleterious effects of cocaine when co-administered with it. Indicative that e.g. the local anesthetic effect at the sigma site mediating the toxicity or otherwise a cross over or tie in of cocaine's separate functionalities lowering threshold to its safety profile.[45]

Polycyclic cage molecules: N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes (AHDs) & related.
The 3-FPh, 14b, has 1.2 ± 0.1 Ki (nM ± SEM) @ DAT.[46]
[[File:(1R,2S,3S,5S,6S,7R,8R,9S,10S)-N-((3-fluorophenyl)methyl)-N-methylpentacyclo(5.4.0.0<sup>2,6</sup>.0<sup>3,10</sup>.0<sup>5,9</sup>)undecan-8-amine.png]]

Bicyclic Amine Analogues

Quinuclidine Analogues


Dihydroimidazoles

Possible substitutions of the Mazindol molecular structure.

See: List of Mazindol analogues

Mazindol is usually considered a non-habituating (in humans, and some other mammals, but is habituating for e.g. Beagles[lower-alpha 44]) tetracyclic dopamine reuptake inhibitor (of somewhat spurious classification in the former).

It is a loosely functional analog used in cocaine research; due in large part to N-Ethylmaleimide being able to inhibit approximately 95% of the specific binding of [3H]Mazindol to the residues of the MAT binding site(s), however said effect of 10 mM N-Ethylmaleimide was prevented in its entirety by just 10 μM cocaine. Whereas neither 300 μM dopamine or D-amphetamine afforded sufficient protection to contrast the efficacy of cocaine.[lower-alpha 45]

The above steps in its synthesis show the similitude of its precursors to the MAT reuptake inhibitor pipradrol & related compounds.

Local anesthetics (not usually CNS stimulants)

Amylocaine, or Stovaine (above), the first synthetically constructed local anesthetic. Compare structure to dimethylaminopivalophenone (below), an analgesic (opioid). Cocaine's classification as a narcotic under U.S. legal code, as has been stretched to be medicinally rationalized such when defining terms very broadly (due to its topical numbing affect, hindering pain signals from CNS recognition via local anesthesia) usually considered an exaggeration of traditional medicine naming convention, in this instance between the first synthetic sodium channel blocker and one of the very simplest opioids there remains a measure of apparent structural similarity between the former anesthetic and latter analgesic "narcotic"; despite the highly differing methods of action for the respective 'pain-killing' properties of either.[47]
β-Eucaine (Betacain)

In animal studies, certain of the local anesthetics have displayed residual dopamine reuptake inhibitor properties,[48] although not normally ones that are easily available. These are expected to be more cardiotoxic than phenyltropanes. For example, dimethocaine has behavioral stimulant effects (and therefore not here listed below) if a dose of it is taken that is 10 times the amount of cocaine. Dimethocaine is equipotent to cocaine in terms of its anesthetic equivalency.[48] Intralipid "rescue" has been shown to reverse the cardiotoxic effects of sodium channel blockers and presumably those effects when from cocaine administered intravenously as well.

List of local anesthetics
Name Other common names
AmylocaineStovaine
ArticaineAstracaine, Septanest, Septocaine, Ultracaine, Zorcaine
Benzocaine
BupivacaineMarcaine, Sensorcaine, Vivacaine
Butacaine
Carticaine
ChloroprocaineNesacaine
Cinchocaine/DibucaineCincain, Cinchocaine, Nupercainal, Nupercaine, Sovcaine
CyclomethycaineSurfacaine, Topocaine
Etidocaine
Eucaineα-eucaine, β-eucaine
Fomocaine[49]
Fotocaine[49]
HexylcaineCyclaine, Osmocaine
LevobupivacaineChirocaine
Lidocaine/LignocaineXylocaine, Betacaine
MepivacaineCarbocaine, Polocaine
Meprylcaine/OracaineEpirocain
MetabutoxycainePrimacaine
Phenacaine/Holocaine
PiperocaineMetycaine
Pramocaine/Pramoxine
PrilocaineCitanest
Propoxycaine/Ravocaine
Procaine/NovocaineBorocaine (Procaine Borate), Ethocaine
Proparacaine/Alcaine
QuinisocaineDimethisoquin
Risocaine
RopivacaineNaropin
Tetracaine/AmethocainePontocaine, Dicaine
TrimecaineMesdicain, Mesocain, Mesokain

See also

Cocaine-N-oxide: Hydroxytropacocaine: m-Hydroxybenzoylecgonine:

Methylecgonine cinnamate, an alkaloid widely considered inactive in its own right, but postulated to be active under pyrolysis. (cf. alkylphenyltropane analogue "224e") It is, however, found in patents of active cocaine analogue structures.[50][51]
Cocaine HCl hydrolyzes in moist air and enucleates from on its tropane-skeleton arrangement to become the above compound; methyl benzoate

Common analogues to prototypical D-RAs:

Notes (inclu. specific locations of citations from within references used)

  1. [1]Page #969 (45th page of article) §III. ¶1. Final line. Last sentence.
  2. [1]Page #1,018 (94th page of article) 2nd column, 2nd paragraph.
  3. [1]Page #940 (16th page of article) underneath Table 8., above §4
  4. [1]Page #970 (46th page of article) Table 27. Figure 29.
  5. [1]Page #971 (47th page of article) Figure 30. & Page #973 (49th page of article) Table 28.
  6. [1]Page #982 (58th page of article)
  7. [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  8. [1]Page #972 (48th page of article) ¶2, Line 10.
  9. [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  10. [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  11. [1]Page #971 (47th page of article) Figure 30 & Page #971 (47th page of article) Figure 30 & Page #973 (49th page of article) Table 28
  12. [1]Page #974 (50st page of article) First (left) column, third ¶
  13. [1]Page #937 (13th page of article) Second (right) column, first ¶. Above/before §2
  14. [1]Page #974 (50th page of article) Final ¶ (5th), Second line.
  15. [1]Page #975 (51st page of article) First ¶, first line.
  16. [1]Page #975 (51st page of article) First ¶, 4th line.
  17. [1]Page #973 (49th page of article) §C. & Page #974 (50th page of article) Figure 31 & Page #976 (52nd page of article) Table 29.
  18. [1]Page #974 (50st page of article) First (left) column, fourth ¶
  19. [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  20. [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  21. [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  22. [1]Page #974 (50th page of article) Figure 31 & Page #977 (53rd page of article) Table 30.
  23. [1]Page #978 (54th page of article) §D & Page #980 (56th page of article) Figure 33 & Page #981 (57th page of article) Table 32.
  24. [1]Page #980 (56th page of article) Scheme 52.
  25. [1]Page #963 (39th page of article) 2nd (right side) column, 2nd paragraph.
  26. [1]Page #982 (58th page of article) §G & Page #983 (59th page of article) Figure 36 & Page #984 (60th page of article) Table 35.
  27. [1]Page #979 (55th page of article) Table 31.
  28. [1]Page #981 (57th page of article) §E & Page #982 (58th page of article) Table 33.
  29. [1]Page #970 (46th page of article) §B, 10th line
  30. [1]Page #971 (47th page of article) 1st ¶, 10th line
  31. [1]Page #949 (25th page of article) 3rd ¶, 20th line
  32. [1]Page #982 (58th page of article) 3rd ¶, lines 2, 5 & 6.
  33. [1]Page #982 (58th page of article) §F, Table 34 & Figure 35.
  34. [1]Page #984 (60th page of article) §H, Figure 37 & Page #985 (61st page of article) Table 36.
  35. [1]Page #984 (60th page of article) Scheme 56.
  36. [1]Page #986 (62nd page of article) §I, Table 37 & Scheme 58
  37. [1]Page #1,014 (90th page of article) §VIII, A. Figure 59.
  38. [1]Page #1,016 (92nd page of article) Figure 60.
  39. [1]Page #987 (63rd page of article) §IV, Figure 39 & Page #988 (64th page of article) Table 38.
  40. [1]Page #987 (63rd page of article) Figure 40, Page #988 (64th page of article) §B & Page #989 (65th page of article) Table 39.
  41. [1]Page #987 (63rd page of article) Figure 41, Page #989 (65th page of article) §C & Page #990 (66th page of article) Table 40.
  42. [1]Page #988 (64th page of article) Figure 42, Page #990 (66th page of article) §2 & Page #992 (68th page of article) Table 41.
  43. [1]Page #988 (64th page of article) Figure 43, Page #992 (68th page of article) §3 & Table 42.
  44. [1]Page #1,011 (87th page of article) §VII (7) 1st ¶.
  45. [1]Page #969 (45th page of article) 2nd (right-side) column 2nd .

References

  1. Singh, Satendra; et al. (2000). "Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists" (PDF). Chem. Rev. 100 (3): 925–1024. doi:10.1021/cr9700538. PMID 11749256.
  2. Watson-Williams, E (1925). "Psicaine: An Artificial Cocaine". Br Med J. 1 (3340): 11. doi:10.1136/bmj.1.3340.11. PMC 2196615. PMID 20771843.
  3. Singh, S; Basmadjian, GP; Avor, K; Pouw, B; Seale, TW (1997). "A convenient synthesis of 2?- or 4?-hydroxycocaine". Synthetic Communications. 27 (22): 4003–4012. doi:10.1080/00397919708005923.
    et. el-Moselhy, TF; Avor, KS; Basmadjian, GP (Sep 2001). "2?-substituted analogs of cocaine: synthesis and dopamine transporter binding potencies". Archiv der Pharmazie (Weinheim). 334 (8–9): 275–8. doi:10.1002/1521-4184(200109)334:8/9<275::aid-ardp275>3.0.co;2-b. PMID 11688137.
    et. Seale, TW; Avor, K; Singh, S; Hall, N; Chan, HM; Basmadjian, GP (1997). "2?-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding". NeuroReport. 8 (16): 3571–5. doi:10.1097/00001756-199711100-00030. PMID 9427328.
  4. Smith, RM; Poquette, MA; Smith, PJ (1984). "Hydroxymethoxybenzoylmethylecgonines: New metabolites of cocaine from human urine". Journal of Analytical Toxicology. 8 (1): 29–34. doi:10.1093/jat/8.1.29. PMID 6708474.
  5. Gatley SJ, Yu DW, Fowler JS, MacGregor RR, Schlyer DJ, Dewey SL, Wolf AP, Martin T, Shea CE, Volkow ND (March 1994). "Studies with differentially labeled [11C]cocaine, [11C]norcocaine, [11C]benzoylecgonine, and [11C]- and 4′-[18F]fluorococaine to probe the extent to which [11C]cocaine metabolites contribute to PET images of the baboon brain". Journal of Neurochemistry. 62 (3): 1154–62. doi:10.1046/j.1471-4159.1994.62031154.x. PMID 8113802.
  6. Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. (1992). "Cocaine Receptor: Biochemical Characterization and Structure-Activity Relationships of Cocaine Analogues at Dopamine Transporter". Journal of Medicinal Chemistry. 35 (6): 969–981. doi:10.1021/jm00084a001. PMID 1552510.
  7. Seale, TW; Avor, K; Singh, S; Hall, N; Chan, HM; Basmadjian, GP (1997). "2′-Substitution of cocaine selectively enhances dopamine and norepinephrine transporter binding". NeuroReport. 8 (16): 3571–5. doi:10.1097/00001756-199711100-00030. PMID 9427328.
  8. Buckett, W. R.; Farquharson, Muriel E.; Haining, C. G. (1964). "The analgesic properties of some 14-substituted derivatives of codeine and codeinone". J. Pharm. Pharmacol. 16 (3): 174–182. doi:10.1111/j.2042-7158.1964.tb07440.x. PMID 14163981.
  9. Sakamuri, Sukumar; et al. (2000). "Synthesis of novel spirocyclic cocaine analogs using the Suzuki coupling". Tetrahedron Letters. 41 (13): 2055–2058. doi:10.1016/S0040-4039(00)00113-1.
  10. Isomura, Shigeki; Hoffman, Timothy Z.; Wirsching, Peter; Janda, Kim D. (2002). "Benzoylthio-. cocaine, analogue substitution. Synthesis, Properties, and Reactivity of Cocaine Benzoylthio Ester Possessing the Cocaine Absolute Configuration". J. Am. Chem. Soc. 124 (14): 3661–3668. doi:10.1021/ja012376y. PMID 11929256.
  11. Davis, Franklin A.; Gaddiraju, Narendra V.; Theddu, Naresh; Hummel, Joshua R.; Kondaveeti, Sandeep K.; Zdilla, Michael J. (2012). "Enantioselective Synthesis of Cocaine C-1 Analogues using Sulfinimines (N-Sulfinyl Imines)". The Journal of Organic Chemistry. 77 (5): 2345–2359. doi:10.1021/jo202652f. ISSN 0022-3263. PMID 22300308.
  12. Reith, M. E. A.; Ali, S.; Hashim, A.; Sheikh, I. S.; Theddu, N.; Gaddiraju, N. V.; Mehrotra, S.; Schmitt, K. C.; Murray, T. F.; Sershen, H.; Unterwald, E. M.; Davis, F. A. (2012). "Novel C-1 Substituted Cocaine Analogs Unlike Cocaine or Benztropine". Journal of Pharmacology and Experimental Therapeutics. 343 (2): 413–425. doi:10.1124/jpet.112.193771. ISSN 1521-0103. PMC 3477221. PMID 22895898. Full article
  13. Sharkey, J; Glen, KA; Wolfe, S; Kuhar, MJ (1988). "Cocaine binding at sigma receptors". Eur J Pharmacol. 149 (1–2): 171–4. doi:10.1016/0014-2999(88)90058-1. PMID 2840298.
  14. Nuwayhid, Samer J.; Werling, Linda L. (2006). "Sigma2 (σ2) receptors as a target for cocaine action in the rat striatum". European Journal of Pharmacology. 535 (1–3): 98–103. doi:10.1016/j.ejphar.2005.12.077. ISSN 0014-2999. PMID 16480713.
  15. Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference: Possible Dependence on Dopamine Uptake Blockade Pascal Romieu et al. Neuropsychopharmacology (2002) 26 444-455.10.1038/S0893-133X(01)00391-8
  16. Yoshihiro Hamaya, Hesham Abdelrazek, Gary R. Strichartz (2002). "A-854: Comparative Potency for Impulse-Blockade and for Cutaneous Analgesia of Traditional and Novel Local Anesthetics". Abstracts of American Society of Anesthesiologists Annual Meeting. ...hydroxypropylbenzoylecgonine (HPBE) is the only effective analgesic compound in [Esterom].CS1 maint: multiple names: authors list (link)
  17. U.S. Patent 6,479,509
  18. Kozikowski, A. P.; Simoni, D.; Roberti, M.; Rondanin, R.; Wang, S.; Du, P.; Johnson, K. M. (1999). "Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity". Bioorganic & Medicinal Chemistry Letters. 9 (13): 1831–1836. doi:10.1016/S0960-894X(99)00273-5. PMID 10406650.
  19. Hoepping, Alexander (2000). "Novel Conformationally Constrained Tropane Analogues by 6- e ndo-trig Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter". Journal of Medicinal Chemistry. 43 (10): 2064–2071. doi:10.1021/jm0001121. PMID 10821718.
  20. Zhang, Ao (2002). "Thiophene derivatives: a new series of potent norepinephrine and serotonin reuptake inhibitors". Bioorganic. 12 (7): 993–995. doi:10.1016/S0960-894X(02)00103-8. PMID 11909701.
  21. Zhang, Ao (2002). "Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites: Synthesis of ( Z )-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0 3,7 ]decanes as a Novel Class of Serotonin Transporter Inhibitors". Journal of Medicinal Chemistry. 45 (9): 1930–1941. doi:10.1021/jm0105373. PMID 11960503.
  22. Davies, HM; Saikali, E; Sexton, T; Childers, SR (1993). "Novel 2-substituted cocaine analogs: binding properties at dopamine transport sites in rat striatum". Eur. J. Pharmacol. 244 (1): 93–7. doi:10.1016/0922-4106(93)90063-f. PMID 8420793.
  23. "Drugbank website "drug card", "(DB00907)" for Cocaine: Giving ten targets of the molecule in vivo, including dopamine/serotonin sodium channel affinity & K-opioid affinity". Drugbank.ca. Retrieved 9 March 2010.
  24. Sahlholm, Kristoffer; Nilsson, Johanna; Marcellino, Daniel; Fuxe, Kjell; Århem, Peter (2012). "Voltage sensitivities and deactivation kinetics of histamine H3 and H4 receptors". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1818 (12): 3081–3089. doi:10.1016/j.bbamem.2012.07.027. PMID 22885137. ...Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors...
  25. Enantioselective synthesis of strobamine and its analogues Xing Zhang et al. Center for Organic and Medicinal Chemistry, Research Triangle Institute. Issue in Honor of Prof. James M.Cook ARKIVOC 2010 (iv)96-103
  26. The Alkaloids; Vol. 44, Geoffrey Cordell
  27. Appell, Michael; Dunn, William J.; Reith, Maarten E.A.; Miller, Larry; Flippen-Anderson, Judith L. (2002). "An Analysis of the Binding of Cocaine Analogues to the Monoamine Transporters Using Tensor Decomposition 3-D QSAR". Bioorganic & Medicinal Chemistry. 10 (5): 1197–1206. doi:10.1016/S0968-0896(01)00389-3. ISSN 0968-0896. PMID 11886784.
  28. Hicks, MJ; De, BP; Rosenberg, JB; Davidson, JT; Moreno, AY; Janda, KD; Wee, S; Koob, GF; Hackett, NR; Kaminsky, SM; Worgall, S; Toth, M; Mezey, JG; Crystal, RG (2011). "Cocaine analog coupled to disrupted adenovirus: a vaccine strategy to evoke high-titer immunity against addictive drugs". Mol Ther. 19 (3): 612–9. doi:10.1038/mt.2010.280. PMC 3048190. PMID 21206484.
  29. Kinsey, BM; Kosten, TR; Orson, FM (2010). "Active immunotherapy for the Treatment of Cocaine Dependence". Drugs of the Future. 35 (4): 301–306. doi:10.1358/dof.2010.035.04.1474292. PMC 3142961. PMID 21796226.
  30. Wee, S; Hicks, MJ; De, BP; Rosenberg, JB; Moreno, AY; Kaminsky, SM; Janda, KD; Crystal, RG; Koob, GF (2011). "Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects". Neuropsychopharmacology. 37 (5): 1083–91. doi:10.1038/npp.2011.200. PMC 3306868. PMID 21918504.
  31. Catalytic antibodies against cocaine and methods of using and producing same Google patents US 6566084 B1
  32. Deng, Shixian; Bharat, Narine; de Prada, Paloma; Landry, Donald W. (2004). "Substrate-assisted antibody catalysis". Organic & Biomolecular Chemistry. 2 (3): 288–90. doi:10.1039/b314264g. ISSN 1477-0520. PMID 14747854.
  33. Ho, M; Segre, M (2003). "Inhibition of cocaine binding to the human dopamine transporter by a single chain anti-idiotypic antibody: its cloning, expression, and functional properties". Biochim Biophys Acta. 1638 (3): 257–66. doi:10.1016/s0925-4439(03)00091-7. PMC 3295240. PMID 12878327.
  34. Schabacker, DS; Kirschbaum, KS; Segre, M (2000). "Exploring the feasibility of an anti-idiotypic cocaine vaccine: analysis of the specificity of anticocaine antibodies (Ab1) capable of inducing Ab2beta anti-idiotypic antibodies". Immunology. 100 (1): 48–56. doi:10.1046/j.1365-2567.2000.00004.x. PMC 2326984. PMID 10809958.
  35. Zhou, Jia; He, Rong; Johnson, Kenneth M.; Ye, Yanping; Kozikowski, Alan P. (2004). "Piperidine-Based Nocaine/Modafinil Hybrid Ligands as Highly Potent Monoamine Transporter Inhibitors: Efficient Drug Discovery by Rational Lead Hybridization". Journal of Medicinal Chemistry. 47 (24): 5821–5824. doi:10.1021/jm040117o. ISSN 0022-2623. PMC 1395211. PMID 15537337.
  36. Skeptics Stack Exchange: Is sugar one element away from cocaine (or any other drug?)
  37. Velázquez-Sánchez, Clara; García-Verdugo, José M.; Murga, Juan; Canales, Juan J. (2013). "The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 44: 73–80. doi:10.1016/j.pnpbp.2013.01.016. ISSN 0278-5846. PMID 23385166.
  38. Tanda, G; Newman, A; Ebbs, AL; Tronci, V; Green, J; Tallarida, RJ; Katz, JL (2009). "Combinations of Cocaine with other Dopamine Uptake Inhibitors: Assessment of Additivity". J Pharmacol Exp Ther. 330 (3): 802–9. doi:10.1124/jpet.109.154302. PMC 2729796. PMID 19483071.
  39. Schmitt, KC; Rothman, RB; Reith, ME (2013). "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". J. Pharmacol. Exp. Ther. 346 (1): 2–10. doi:10.1124/jpet.111.191056. PMC 3684841. PMID 23568856.
  40. Rothman, RB; Baumann, MH; Prisinzano, TE; Newman, AH (2008). "Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction". Biochem Pharmacol. 75 (1): 2–16. doi:10.1016/j.bcp.2007.08.007. PMC 2225585. PMID 17897630.
  41. Runyon, SP; Carroll, FI (2006). "Dopamine transporter ligands: recent developments and therapeutic potential". Curr Top Med Chem. 6 (17): 1825–43. doi:10.2174/156802606778249775. PMID 17017960.
  42. Loland, C. J.; Desai, R. I.; Zou, M.-F.; Cao, J.; Grundt, P.; Gerstbrein, K.; Sitte, H. H.; Newman, A. H.; Katz, J. L.; Gether, U. (2007). "Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors". Molecular Pharmacology. 73 (3): 813–823. doi:10.1124/mol.107.039800. ISSN 0026-895X. PMID 17978168.
  43. Dallanoce, Clelia; Canovi, Mara; Matera, Carlo; Mennini, Tiziana; De Amici, Marco; Gobbi, Marco; De Micheli, Carlo (2012). "A novel spirocyclic tropanyl-Δ2-isoxazoline derivative enhances citalopram and paroxetine binding to serotonin transporters as well as serotonin uptake". Bioorganic & Medicinal Chemistry. 20 (21): 6344–6355. doi:10.1016/j.bmc.2012.09.004. ISSN 0968-0896. PMID 23022052.
  44. C. Dallanoce et al. - Bioorg. Med. Chem. 20 (2012) 6344-6355
  45. Xu, Y. T.; Kaushal, N.; Shaikh, J.; Wilson, L. L.; Mesangeau, C.; McCurdy, C. R.; Matsumoto, R. R. (2010). "A Novel Substituted Piperazine, CM156, Attenuates the Stimulant and Toxic Effects of Cocaine in Mice". Journal of Pharmacology and Experimental Therapeutics. 333 (2): 491–500. doi:10.1124/jpet.109.161398. ISSN 0022-3565. PMC 2872963. PMID 20100904.
  46. Banister, Samuel D.; Manoli, Miral; Barron, Melissa L.; Werry, Eryn L.; Kassiou, Michael (2013). "N-substituted 8-aminopentacyclo[5.4.0.02,6.03,10.05,9]undecanes as σ receptor ligands with potential neuroprotective effects". Bioorganic & Medicinal Chemistry. 21 (19): 6038–6052. doi:10.1016/j.bmc.2013.07.045. ISSN 0968-0896. PMID 23981939.
  47. Ruetsch, YA; Böni, T; Borgeat, A (Aug 2001). "From cocaine to ropivacaine: the history of local anesthetic drugs". Curr Top Med Chem. 1 (3): 175–82. doi:10.2174/1568026013395335. PMID 11895133.
  48. Wilcox, K.M.; Kimmel, H.L.; Lindsey, K.P.; Votaw, J.R.; Goodman, M.M.; Howell, L.L. (2005). "In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys" (PDF). Synapse. 58 (4): 220–228. CiteSeerX 10.1.1.327.1264. doi:10.1002/syn.20199. PMID 16206183. Archived from the original (PDF) on 2010-06-11.
  49. Schoenberger, Matthias; Damijonaitis, Arunas; Zhang, Zinan; Nagel, Daniel; Trauner, Dirk (2014). "Development of a New Photochromic Ion Channel Blocker via Azologization of Fomocaine". ACS Chemical Neuroscience. 5 (7): 514–518. doi:10.1021/cn500070w. ISSN 1948-7193. PMC 4102962. PMID 24856540. nih.gov article
  50. U.S. Patent 6,479,509 Patent inventor Frank Ivy Carroll, Assignee: Research Triangle Institute
  51. U.S. patent US6479509 B1 structures given for submission, 5th compound down in image.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.