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| Other names | 3-(1,2-dimethylheptyl)-Δ6a(10a)-THC, 1,2-dimethylheptyl-Δ3-THC, A-40824, EA-2233 |
| Drug class | Cannabinoid |
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| Eliminationhalf-life | 20–39 hours |
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| Chemical and physical data | |
| Formula | C25H38O2 |
| Molar mass | 370.577 g·mol−1 |
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Dimethylheptylpyran (DMHP) is asynthetic cannabinoid andanalogue oftetrahydrocannabinol (THC). It was invented in 1949 during attempts to elucidate the structure of Δ9-THC, one of the active components ofcannabis.[2] DMHP is a pale yellow, viscous oil which is insoluble in water but dissolves in alcohol or non-polar solvents.
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.[3]
DMHP produces similar activity to THC, such assedative effects, but is considerably more potent,[4] especially having much strongeranalgesic andanticonvulsant effects than THC, although comparatively weaker psychological effects.
It is thought to act as aCB1 receptoragonist, in a similar manner to othercannabinoid derivatives.[5][6] While DMHP itself has been subject to relatively little study since the characterization 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.[7]
| 7 double bond isomers of dimethylheptylpyran and their 120 stereoisomers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Dibenzopyran numbering | Monoterpenoid numbering | Additional chiral centers on side chain | Number of stereoisomers | Natural occurrence | Convention on Psychotropic Substances Schedule | ||||
| Short name | Chiral centers in dibenzopyran backbone | Full name | Short name | Chiral centers in dibenzopyran backbone | 1,2-dimethylheptyl numbering | 3-methyloctan-2-yl numbering | |||
| Δ6a(7)-DMHP | 9 and 10a | 3-(1,2-dimethylheptyl)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ4-DMHP | 1 and 3 | 1 and 2 | 2 and 3 | 16 | No | unscheduled |
| Δ7-DMHP | 6a, 9 and 10a | 3-(1,2-dimethylheptyl)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ5-DMHP | 1, 3 and 4 | 1 and 2 | 2 and 3 | 32 | No | unscheduled |
| Δ8-DMHP | 6a and 10a | 3-(1,2-dimethylheptyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ6-DMHP | 3 and 4 | 1 and 2 | 2 and 3 | 16 | No | unscheduled |
| Δ9,11-DMHP | 6a and 10a | 3-(1,2-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-6H-dibenzo[b,d]pyran-1-ol | Δ1(7)-DMHP | 3 and 4 | 1 and 2 | 2 and 3 | 16 | No | unscheduled |
| Δ9-DMHP | 6a and 10a | 3-(1,2-dimethylheptyl)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ1-DMHP | 3 and 4 | 1 and 2 | 2 and 3 | 16 | No | unscheduled |
| Δ10-DMHP | 6a and 9 | 3-(1,2-dimethylheptyl)-6a,7,8,9-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ2-DMHP | 1 and 4 | 1 and 2 | 2 and 3 | 16 | No | unscheduled |
| Δ6a(10a)-DMHP | 9 | 3-(1,2-dimethylheptyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol | Δ3-DMHP | 1 | 1 and 2 | 2 and 3 | 8 | No | Schedule I |
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-benzo[c]chromen-1-ol.
The fiscal budgeting and planning for Edgewood Arsenal (established in 1948) considered it to be primarily a defensive research facility. The US military, at the time, knew that theUSSR was spending 10 times more than the USA on chemical weapons development. Edgewood initially enjoyed a mandate[clarification needed] and lack of oversight. Edgewood Arsenal Chemical Corps was tasked with ensuring that America was prepared with adequate counter-tactics if needed and that it could mount its own psychochemical retaliatory strike against the USSR if necessary. Edgewood performed analysis and submitted data to military commanders who could then choose to incorporate that into their strategy. In practice, however, it was mostly to make the strategists aware of special weapons and tactics that the enemy could instead deploy.
The Edgewood Laboratory was originally founded in 1948. The originalcannabinoid distillate (the precursor to EA-2233, called EA-1476 or "Red oil"), known today asdelta-9-THC, was first created in 1949, and laboratory study of EA-1476 occurred in the mid-1950s. A single batch of EA-2233 was prepared by chemist Harry Pars of A.D. Little Labs in 1962 under a top-secret government contract. It was administered to groups of consenting & informed[citation needed] enlisted servicemen by Dr.James Ketchum in 1962. The Edgewood laboratory was shut down in 1975. Government funding for continued military development of synthetic cannabis was lacking and the cannabinoid research program was indefinitely suspended along with the rest of the Edgewood Arsenal experiments in the late 1970s for a variety of reasons. There was growing public distrust of the military and government, and there was little useful purpose for the further development of chemical incapacitating agents during and after the Vietnam era.[8]
Multiple newspapers criticized the EA-2233 experiments. Since the 1930s, cannabis and cannabinoids had consistently been seen by the public as dangerous and addictive drugs. DMHP was compared to BZ, a non-cannabis chemical that was cited to be useless among military planners, and was only tested once in a hastily constructed operation called "Project Dork" (part ofProject 112).[9]
DMHP and itsO-acetateester were extensively investigated by theUS military chemical weapons program in theEdgewood Arsenal experiments, as possible non-lethal incapacitating agents.[10]
DMHP has threestereocenters and consequently has eight possiblestereoisomers, which differ considerably in potency. The mixture of all eight isomers of theO-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 is 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 metabolized in a similar manner to THC, producing the active metabolite 11-hydroxy-DMHP, but thelipophilicity 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 producesedation and mildhallucinogenic effects similar to large doses ofTHC. However, they also cause pronouncedhypotension (low blood pressure), occurring at doses well below the hallucinogenic dose, which can lead to severedizziness,fainting,ataxia andmuscle weakness, sufficient to make it difficult to stand upright or carry out any kind of vigorous physical activity.[8]
The acute toxicity of DMHP was found to be low in both human and animal studies, with thetherapeutic index measured as a ratio ofED50 toLD50 in animals being around 2000 times. There have been no recorded deaths caused by any DMHP EA-2233 stereoisomers 1–8, only symptoms that are entirely consistent with the highest-known levels of THC intoxication.[8] DMHP has an intravenous LD50 of 63 mg/kg in mice and an intravenous minimal lethal dose of 10 mg/kg in dogs.[11]
The combination of strong incapacitating effects and a favorable 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, DMHP had the disadvantage of sometimes producing severehypotension at pre-incapacitating doses, which did not occur with the more widely studied and publicized belladonnoidanticholinergic agents, such as3-Quinuclidinyl benzilate (BZ), which was discovered and subsequently weaponized.[12] Military applications of synthetic cannabinoids were limited because the drug was both illegal and politically toxic to study via laboratory administration to enlisted servicemen. Both EA-2233-2 and the red-oil THC distillate predecessor, EA-1476, received limited budget and resources compared to the study of other incapacitating agents of BZ derivatives andLSD, (which was widely believed at the time to be a viable mind-control andtruth serum useful in a variety of Cold War applications).[8] Initially, the 8 stereoisomers of EA-2233 could not be separated; later, two of the individual isomers of EA-2233 were isolated and tested, but were found to cause bothorthostatic hypotension and minimal effects on performance at the very low doses used. EA-2233 did not seem to have sufficient potency to be of military interest, since an oral dose of 60mcg/kg caused a maximum decline of only 40% (at most) in performance at language and number processing tasks.
