Dimethylheptylpyran

Dimethylheptylpyran
Clinical data
ATC code
  • none
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • DE: Anlage I (Authorized scientific use only)
  • UK: Class B
  • US: Schedule I
Pharmacokinetic data
Elimination half-life20–39 hours
Identifiers
IUPAC name
  • 6,6,9-Trimethyl-3-(3-methyl-2-octanyl)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-1-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H38O2
Molar mass370.577 g·mol−1
3D model (JSmol)
SMILES
  • CCCCCC(C)C(C)c1cc(c2c(c1)OC(C3=C2CC(CC3)C)(C)C)O
InChI
  • InChI=1S/C25H38O2/c1-7-8-9-10-17(3)18(4)19-14-22(26)24-20-13-16(2)11-12-21(20)25(5,6)27-23(24)15-19/h14-18,26H,7-13H2,1-6H3 ☒N
  • Key:QBEFIFWEOSUTKV-UHFFFAOYSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

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.

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.[8] 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, there have been no recorded deaths caused by any DMHP EA-2233 stereoisomers 1–8, only symptoms that are entirely consistent with highest-known levels of THC intoxication.[8]

Unsuitability for military application

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 DMHP was disadvantaged by sometimes producing severe hypotension at pre-incapacitating doses, which did not occur with the more widely studied & publicised belladonnoid anticholinergic agents such as 3-Quinuclidinyl benzilate (BZ) that was discovered and subsequently weaponized.[9] Military applications of synthetic cannabis were limited because the drug was both illegal and politically toxic to study via laboratory administration to enlisted servicemen. According to the memoirs of supervising Colonel Dr. James Ketchum, who describes performing the experiments in Chapter 5 of his book titled "Chemical Warfare Secrets Almost Forgotten" both EA-2233-2 and the red-oil THC distillate predecessor (called EA-1476) both received limited budget and resources when compared to the study of other incapacitating agents of BZ derivatives and EA 1729 (LSD) which was widely believed at the time to be a viable mind-control and truth serum useful in a variety of Cold War applications. Initially the 8 stereoisomers of EA-2233 could not be separated, later Dr. Sidell was later able to isolate and test two of the individual isomers of EA 2233 but found them to cause both orthostatic 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 TF word & number facility performance. Doctor Hollister later published a study which showed that the oral effects of ordinary THC were only about one-third that of THC smoked as marijuana. The Hollister study suggests that effectiveness of EA 2233 in an aerosol might be much greater than by the oral route, however this has never been independently verified using DMHP EA 2233. EA 2233 has never been used outside the walls of the Baltimore Edgewood Arsenal where it caused zero deaths, but was theorized to be able to pose risk to those either very young, very old, or could cause loss of motor skills in those with pre-existing hypotension. In all cases Dr. Ketchum reported that after 72 hours all those which survived (100%) showed no detectable residual effects, flashbacks, etc.

However, because DMHP was deemed to have an unsafe TI (Therapeutic Index) relative to BZ for use during military operations, its study was abandoned in favor of BZ.

Edgewood Arsenal & EA 2233

The fiscal budgeting and planning for Edgewood Arsenal (established in 1948) was primarily a defensive research facility. US Military commands at the time knew that the USSR (the Cold-war adversary of the USA) was spending 10x more than the USA on chemical weapons development. Edgewood initially enjoyed a mandate and lack of oversight. Edgewood Arsenal Chemical Corps was tasked with insuring America was prepared with adequate counter-tactics and could mount its own psychochemical retaliatory strike if necessary. Edgewood preformed analysis and submitted data to military commanders who could then choose to incorporate that into strategy (although in context, it was mostly to make the strategists aware of special weapons and tactics the enemy could deploy).

The Edgewood laboratory was originally founded at the tail end of WW-II in 1948. The original (precursor to EA 2233, called EA-1476) or "Red oil" known today as THC Delta-9 Distillate was first created in 1949, and laboratory study of EA-1476 occurred in the mid-1950's. 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 and it was administered to groups of consenting & informed 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 incredibly rare 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 mostly-political reasons, there was growing public distrust of the military and government, there was a general lack of utility or suitable purpose for deploying chemical incapacitating agents during the era of Vietnam war.[8]

Ultimately the most toxic aspect of EA 2233 was its toxicity for researchers careers due to its designation as synthetic cannabis. EA-2233 was a story the media loved to malign and the military brass loathed to hear about, as such any attention EA-2233 received was always both unfavorable and undesirable. There had been, since the 1930s, an extensive misinformation "smear" campaign for anything related to Cannabis (for example [Reefer Madness]). Thus for straight-laced law-abiding military strategists DMHP was perhaps always the least attractive option, especially when compared to BZ, there was no chance EA 2233 was ever going to get selected for a mission by any commander who desired to maintain or advance in their career. Although BZ was not cannabis, it was also viewed with a lack of imagination and utility among military planners. BZ was only tested once in an hastily constructed operation called "Project Dork".[10] It could be said that military planners of post-WW2 cold-war strategy and tactics favored non-nuclear stale-mate battle scenarios using known conventional explosives, thus a weapons utility and strength was measured using the size of crater it would leave.

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. Total Synthesis of Natural Products. Vol. 4. Wiley-Interscience. pp. 185–262. doi:10.1002/9780470129678.ch2. ISBN 978-0-471-05460-3.
  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 (April 1976). "Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains". Journal of Medicinal Chemistry. 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, Duncan Jr SG, Wiley JL, Martin BR (1997). "Synthesis and pharmacology of the 1′,2′-dimethylheptyl-Δ8-THC isomers: exceptionally potent cannabinoids". Bioorganic & Medicinal Chemistry Letters. 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". Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Vol. 2. Commission on Life Sciences. The National Academies Press. 1984. pp. 79–99. doi:10.17226/9136. ISBN 978-0-309-07772-9.
  8. 1 2 3 Ketchum JS (2006). "Chapter 5". Chemical Warfare: Secrets Almost Forgotten. Santa Rosa, CA: ChemBooks Inc. p. 38. ISBN 978-1-4243-0080-8.
  9. ↑ Ketchum JS (2006). Chemical Warfare Secrets Almost Forgotten. ChemBooks Inc. ISBN 978-1-4243-0080-8.
  10. ↑ Khatchadourian R (12 December 2012). "War of the Mind". The New Yorker. Retrieved 2021-05-08.
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