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Dimethylheptylpyran
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| Systematic (IUPAC) name | |
| 6,6,9-trimethyl-3-(3-methyloctan-2-yl)-
7,8,9,10-tetrahydrobenzo[c]chromen-1-ol |
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| Identifiers | |
| CAS number | |
| ATC code | ? |
| PubChem | |
| Chemical data | |
| Formula | C25H38O2 |
| Mol. mass | 370.57 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | 20-39 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status |
Schedule I / Class A |
| Routes | ? |
Dimethylheptylpyran (1,2-dimethylheptyl-Δ3THC, DMHP, EA-1476) is a synthetic analogue of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, the active component of cannabis.1 DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.
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Effects
DMHP is similar in both 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 similar cannabinoid derivatives.4
Legality
DMHP was made illegal under UN convention in 1982 on the basis of its structural similarity and similar effects profile to THC, despite never having had any recorded instances of abuse by humans or illicit sale. In the United States, DMHP was placed into the most restrictive Schedule I as a compound with no medical use, although it is still used in some scientific research into cannabinoid drugs.
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.5
DMHP has three stereocenters and consequently has eight possible stereoisomers, which differ considerably in potency. The racemic mix 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 to EA-2233-8. The most potent isomer was EA-2233-2, with an active dose range in humans of 0.5-2.8μg/kg (i.e. ~35-200μg for a 70kg adult). Active doses varied markedly between individuals, but when the dose of EA-2233 was taken up to 1-2mg, 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 20-39 hours, with the half life of the 11-hydroxy-DMHP metabolite being longer than 48 hours.
Cannabinoids as a class are generally safe compounds with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating agents. 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 ratio of ED50 to LD50 in animals being around 2000x, 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 most promising non-lethal incapacitating agents to come out of their research program, and indeed were more suitable for development for this application than the more widely publicised anticholinergic agents such as 3-Quinuclidinyl benzilate. However funding for continued development was not approved, and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.
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References
- ^ Adams R, Harfenist M, Loewe S. New Analogs of Tetrahydrocannabinol. XIX. Journal of the American Chemical Society. 1949; 71(5):1624-1628.
- ^ Razdan RK. The Total Synthesis of Cannabinoids. Wiley-Interscience 1980.
- ^ Wilkison DM, Pontzer N, Hosko MJ. "Slowing of cortical somatosensory evoked activity by delta 9-tetrahydrocannabinol and dimethylheptylpyran in alpha-chloralose-anesthetized cats." Neuropharmacology. 1982 Jul;21(7):705-9. PMID 6289158
- ^ Parker LA, Mechoulam R. "Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats." Integrative Physiological and Behavioural Science. 2003 Apr-Jun;38(2):133-45. PMID 14527182
- ^ Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) Commission on Life Sciences. The National Academies Press. pp79-99.
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