Tametraline

Tametraline (CP-24,441) is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline (CP-51,974-1).[1]

Tametraline
Clinical data
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H19N
Molar mass237.346 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Sertraline has been called "3,4-dichloro-tametraline". This is correct but it is an oversimplification in the sense that sertraline is the S,S-isomer whereas tametraline is the 1R,4S-stereoisomer.

1R-Methylamino-4S-phenyl-tetralin is a potent inhibitor of norepinephrine uptake in rat brain synaptosomes,[2] reverses reserpine induced hypothermia in mice, and blocks uptake of 3H-Norepinephrine into rat heart.[3]

Tametraline is a norepinephrine-dopamine reuptake inhibitor.[4]

Indatraline is an indanamine homolog of tetralin-based tametraline, although in the case of indatraline the product is pm-dichlorinated.

Chemistry

Two routes have been previously described,[5] one for aryl moieties containing electron withdrawing groups, and one for electron donating groups:

Preparation of tametraline[6]

"As expected, Friedel-Crafts cyclization of the diarylbutyric acid derivatives # to the most reactive ring was observed with little or none of the alternative isomer being detected."

"The KMnO4 oxidation of the 1-aryl-tetralins # was observed to give 4-hydroxy-4-aryltetralones # instead of the expected tetralone # previously reported.[5] As a result of this finding, direct oxidation of Grignard reaction product # was attempted and found to be a more efficient route."

See also.[6][7][8][9][10]

cis-/trans-Ratio

In the case of 3,4-dichloro product, approximately 50:50 cis-/trans- ratio was achieved, according to the reference.[4]

CAN radical induced dimerization of styrene

"A facile one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile is described."[11][12]

one-pot synthesis of 1-amino-4-aryl-tetralin derivatives by the CAN-induced cyclodimerization of various styrenes in acetonitrile and acrylonitrile

Structure-activity relationship

Certain aromatic substitutients have a potentiating effect (e.g., p-Br), whereas others negate the compound's intrinsic activity.

It is not right to think of the dimethyl analogs as a "prodrug" to the monomethylated drugs (cf. indatraline, "31,345"), but it is correct that it is a "latentiated" form of the drug. This word is from the salsalate page. This was the reason why sertraline was made only as monomethylated because apparently according to the orders the 1° amine is inactive therefore the drug would have a shorter duration of activity.

Enantiopurified trans- and cis-aminotetraline derivatives
"31,345" structure:[13]
Enantiopurified 4-aryl-aminotetralins IC50 (μM)
StereoXYNE DA5-HT
RSHH0.0180.150.84
SRHH0.371.4014.00
RSClH0.0190.0520.084
SRClH0.461.403.50
RSClCl0.010.0440.039
SRClCl0.0440.270.47
SSClCl1.201.300.06
RRClCl0.300.320.46

(±)-Sertraline is not entirely SERT selective until it has been resolved into the S,S-enantiomer.

In terms of the trans- isomers there is relatively marked separation in the activity between the R,S- and S,R-enantiomers. This stands in contrast to what has been observed in the homologous indamine class where both of the trans- enantiomers possessed significant TRI activity at all three of the monoamine transporters.

Racemic cis- and trans-aminotetraline derivatives

The primary amines are claimed to completely lack any affinity for the transporters.

See also

References
  1. Koe BK, Weissman A, Welch WM, Browne RG (September 1983). "Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin". The Journal of Pharmacology and Experimental Therapeutics. 226 (3): 686–700. PMID 6310078.
  2. Koe BK (December 1976). "Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain". The Journal of Pharmacology and Experimental Therapeutics. 199 (3): 649–61. PMID 994022.
  3. Sarges R, Koe BK, Weissman A, Schaefer JP (December 1974). "Blockade of heart 3H-norepinephrine up-take by 4-phenyl-1-aminotetralines: implications for the active conformation of imipramine-like drugs". The Journal of Pharmacology and Experimental Therapeutics. 191 (3): 393–402. PMID 4427286.
  4. Welch WM, Kraska AR, Sarges R, Koe BK (November 1984). "Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins". Journal of Medicinal Chemistry. 27 (11): 1508–15. doi:10.1021/jm00377a021. PMID 6492080.
  5. Sarges R (1975). "Synthesis of phenyl-substituted 1-aminotetralines". The Journal of Organic Chemistry. 40 (9): 1216–1224. doi:10.1021/jo00897a008.
  6. US patent 4045488, Sarges, Reinhard, "Aminophenyltetralin compounds", issued 1977-08-30, assigned to Pfizer Inc.
  7. Johnson WS, Petersen JW, Schneider WP (1947). "Extension of the modified Stobbe condensation. Acid-catalyzed decomposition of the products and a lacto–enoic tautomerism". Journal of the American Chemical Society. 69 (1): 74–79. doi:10.1021/ja01193a020.
  8. Riegel B, Burr JG (March 1948). "Carcinogenic hydrocarbons; 9-11-dimethylbenz [a] anthracene and 8,9,11-trimethylbenz [a] anthracene". Journal of the American Chemical Society. 70 (3): 1070–3. doi:10.1021/ja01183a058. PMID 18909174.
  9. Daub GH, Johnson WS (1950). "The Stobbe condensation with sodium hydride". Journal of the American Chemical Society. 72 (1): 501–504. doi:10.1021/ja01157a130.
  10. Wawzonek S, Kozikowski J (1954). "2-Substituted amino- and aminomethyl-4-phenyl-1-tetralones". Journal of the American Chemical Society. 76 (6): 1641–1643. doi:10.1021/ja01635a052.
  11. Nair V, Rajan R, Rath NP (May 2002). "A CAN-induced cyclodimerization-Ritter trapping strategy for the one-pot synthesis of 1-amino-4-aryltetralins from styrenes". Organic Letters. 4 (9): 1575–7. doi:10.1021/ol0257934. PMID 11975632.
  12. "A CAN-induced cyclodimerization–Ritter trapping strategy for the one-pot synthesis of 1-amino-4-aryltetralins from styrenes: Vijay Nair, Roshini Rajan and Nigam P. Rath". Abstract. Organic Chemistry Portal. Reto Müller. n.d. Retrieved November 10, 2019.
  13. Peng XQ, Xi ZX, Li X, Spiller K, Li J, Chun L, et al. (December 2010). "Is slow-onset long-acting monoamine transport blockade to cocaine as methadone is to heroin? Implication for anti-addiction medications". Neuropsychopharmacology. 35 (13): 2564–78. doi:10.1038/npp.2010.133. PMC 2978747. PMID 20827272.
  14. Rajšner M, Kopicová Z, Holubek J, Svátek E, Metyš J, Bartošová M, Mikšík F, Protiva M (1978). "4,4-Bis(4-fluorophenyl)butylamines and their cyclic analogues; An efficient synthesis of the neuroleptic penfluridol". Collection of Czechoslovak Chemical Communications. 43 (7): 1760–1777. doi:10.1135/cccc19781760. ISSN 0010-0765.
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