Dimethylheptylpyran

Dimethylheptylpyran (DMHP, 3-(1,2-dimethylheptyl)-Δ6a(10a)-THC, 1,2-dimethylheptyl-Δ3-THC, A-40824, or EA-2233) is a synthetic analog of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, one of the active components of Cannabis.[1] DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.

Dimethylheptylpyran
Clinical data
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Elimination half-life20–39 hours
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H38O2
Molar mass370.577 g·mol−1
3D model (JSmol)
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Effects

DMHP is similar in structure to THC, differing only in the position of one double bond, and the replacement of the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain.[2] It produces similar activity to THC, such as sedative effects, but is considerably more potent,[3] especially having much stronger analgesic and anticonvulsant effects than THC, although comparatively weaker psychological effects. It is thought to act as a CB1 agonist, in a similar manner to other cannabinoid derivatives.[4][5] While DMHP itself has been subject to relatively little study since the characterisation of the cannabinoid receptors, the structural isomer 1,2-dimethylheptyl-Δ8-THC has been shown to be a highly potent cannabinoid agonist, and the activity of its enantiomers has been studied separately.[6]

Investigation as non-lethal incapacitating agent

DMHP and its O-acetate ester were extensively investigated by the US military chemical weapons program in the Edgewood Arsenal experiments, as possible non-lethal incapacitating agents.[7]

DMHP has three stereocenters and consequently has eight possible stereoisomers, which differ considerably in potency. The mixture of all eight isomers of the O-acetyl ester was given the code number EA-2233, with the eight individual isomers numbered EA-2233-1 through EA-2233-8. The most potent isomer was EA-2233-2, with an active dose range in humans of 0.5–2.8 μg/kg (i.e. ~35–200 μg for a 70 kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1–2 mg, all volunteers were considered to be incapable of performing military duties, with the effects lasting as long as 2–3 days.

DMHP is metabolised in a similar manner to THC, producing the active metabolite 11-hydroxy-DMHP, but the lipophilicity of DMHP is even higher than that of THC itself, giving it a long duration of action and an extended half-life in the body of between 20 and 39 hours, with the half-life of the 11-hydroxy-DMHP metabolite being longer than 48 hours.

DMHP and its esters produce sedation and mild hallucinogenic effects similar to large doses of THC, but in addition to this they also cause pronounced hypotension (low blood pressure) which occurs at doses well below the hallucinogenic dose, and can lead to severe dizziness, fainting, ataxia and muscle weakness, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity. The acute toxicity of DMHP was found to be low in both human and animal studies, with the therapeutic index measured as a ratio of ED50 to LD50 in animals being around 2000 times, with death ultimately resulting from a combination of hypotension and hypothermia and preventable with supportive treatment.

The combination of strong incapacitating effects and a favourable safety margin led the Edgewood Arsenal team to conclude that DMHP and its derivatives, especially the O-acetyl ester of the most active isomer, EA-2233-2, were among the more promising non-lethal incapacitating agents to come out of their research program. However they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as effective as the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate which had also already been weaponised.[8] Funding for continued development was ultimately not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s.

Isomerism
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
7 double bond isomers of dimethylheptylpyran and their 120 stereoisomers
Dibenzopyran numberingMonoterpenoid numberingAdditional chiral centers on side chainNumber of stereoisomersNatural occurrenceConvention on Psychotropic Substances Schedule
Short nameChiral centers in dibenzopyran backboneFull nameShort nameChiral centers in dibenzopyran backbone1,2-dimethylheptyl numbering3-methyloctan-2-yl numbering
Δ6a(7)-DMHP9 and 10a3-(1,2-dimethylheptyl)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ4-DMHP1 and 31 and 22 and 316Nounscheduled
Δ7-DMHP6a, 9 and 10a3-(1,2-dimethylheptyl)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ5-DMHP1, 3 and 41 and 22 and 332Nounscheduled
Δ8-DMHP6a and 10a3-(1,2-dimethylheptyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ6-DMHP3 and 41 and 22 and 316Nounscheduled
Δ9,11-DMHP6a and 10a3-(1,2-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-6H-dibenzo[b,d]pyran-1-olΔ1(7)-DMHP3 and 41 and 22 and 316Nounscheduled
Δ9-DMHP6a and 10a3-(1,2-dimethylheptyl)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ1-DMHP3 and 41 and 22 and 316Nounscheduled
Δ10-DMHP6a and 93-(1,2-dimethylheptyl)-6a,7,8,9-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ2-DMHP1 and 41 and 22 and 316Nounscheduled
Δ6a(10a)-DMHP93-(1,2-dimethylheptyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-olΔ3-DMHP11 and 22 and 38NoSchedule I

Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-benzo[c]chromen-1-ol.

See also

References
  1. Adams R, Harfenist M, Loewe S (1949). "New Analogs of Tetrahydrocannabinol. XIX". Journal of the American Chemical Society. 71 (5): 1624–1628. doi:10.1021/ja01173a023.
  2. Razdan RK (1980). "The Total Synthesis of Cannabinoids". Total Synthesis of Natural Products, Volume 4. Total Synthesis of Natural Products. Wiley-Interscience. pp. 185–262. doi:10.1002/9780470129678.ch2. ISBN 9780471054603.
  3. Wilkison DM, Pontzer N, Hosko MJ (July 1982). "Slowing of cortical somatosensory evoked activity by delta 9-tetrahydrocannabinol and dimethylheptylpyran in alpha-chloralose-anesthetized cats". Neuropharmacology. 21 (7): 705–9. doi:10.1016/0028-3908(82)90014-4. PMID 6289158. S2CID 35663464.
  4. Winn M, Arendsen D, Dodge P, Dren A, Dunnigan D, Hallas R, Hwang K, Kyncl J, Lee YH, Plotnikoff N, Young P, Zaugg H. Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains. J Med Chem. 1976 Apr;19(4):461-71. doi:10.1021/jm00226a003 PMID 817021
  5. Parker LA, Mechoulam R (2003). "Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats". Integrative Physiological and Behavioral Science. 38 (2): 133–45. doi:10.1007/BF02688831. PMID 14527182. S2CID 38974868.
  6. Huffman JW, et al. Synthesis and pharmacology of the 1′,2′-dimethylheptyl-Δ8-THC isomers: exceptionally potent cannabinoids. Bioorganic & Medicinal Chemistry Letters 1997; 7(21): 2799-2804. doi:10.1016/S0960-894X(97)10086-5
  7. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents. Vol. 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Commission on Life Sciences. The National Academies Press. 1984. pp. 79–99.
  8. Ketchum JS (2006). Chemical Warfare Secrets Almost Forgotten. ChemBooks Inc. ISBN 978-1-4243-0080-8..
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