Dimethylheptylpyran

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
Legal status
Legal status	Schedule I / Class A
Pharmacokinetic data
Biological half-life	20-39 hours
Identifiers
CAS Number	32904-22-6
ATC code	none
PubChem	CID 36276
Chemical data
Formula	C25H38O2
Molar mass	370.57 g/mol[[]]

Dimethylheptylpyran (1,2-dimethylheptyl-Δ³THC, DMHP, A-40824, 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. DMHP is a pale yellow, viscous oil which is insoluble in water, but dissolves in alcohol or non-polar solvents.

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. It produces similar activity to THC, such as sedative effects, but is considerably more potent, 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.

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.

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 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 20-39 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 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. 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, in accordance with the US commitment to cease research into chemical weapons under disarmament treaties.