Metazocine Explained

Metazocine is an opioid analgesic related to pentazocine. While metazocine has significant analgesic effects,[1] mediated through a mixed agonist–antagonist action[2] at the mu opioid receptor,[3] its clinical use is limited by dysphoric and hallucinogenic effects which are most likely caused by activity at kappa opioid receptors (where it is a high-efficacy agonist)[4] and/or sigma receptors.[5] [6]

Metazocine is in Schedule II of the Controlled Substances Act 1970 of the United States as a Narcotic with ACSCN 9240 with a 19 gram aggregate manufacturing quota as of 2014. The free base conversion ratio for salts includes 0.81 for the hydrochloride and 0.74 for the hydrobromide.[7] It is listed under the Single Convention for the Control of Narcotic Substances 1961 and is controlled in most countries in the same fashion as is morphine.

Syntheses

The benzomorphan, metazocine (6), can be obtained from a variation of the morphinan synthesis.

Reaction of the Grignard reagent from p-methoxybenzyl chloride (1) with the lutidine methiodide (2) affords the benzylated dihydropyridine (3). Reduction of the enamine π-bond leads to the tetrahydropyridine (4). Cyclization by means of acid leads directly to the benzomorphan ring system (5). Demethylation of the aromatic ring system gives the phenol. Although this last compound is in fact a relatively potent analgesic, it is not available commercially as a drug.[8] [9] Also see:[10]

See also

Notes and References

  1. Hori M, Ban M, Imai E, Iwata N, Suzuki Y, Baba Y, Morita T, Fujimura H, Nozaki M, Niwa M . Novel nonnarcotic analgesics with an improved therapeutic ratio. Structure-activity relationships of 8-(methylthio)- and 8-(acylthio)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines . Journal of Medicinal Chemistry . 28 . 11 . 1656–61 . November 1985 . 2999399 . 10.1021/jm00149a020 .
  2. Berzetei-Gurske I, Loew GH . The novel antagonist profile of (-)metazocine . Progress in Clinical and Biological Research . 328 . 33–6 . 1990 . 2154788 .
  3. Gharagozlou P, Demirci H, David Clark J, Lameh J . Activity of opioid ligands in cells expressing cloned mu opioid receptors . BMC Pharmacology . 3 . 1 . January 2003 . 12513698 . 140036 . 10.1186/1471-2210-3-1 . free .
  4. Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J . Pharmacological profiles of opioid ligands at kappa opioid receptors . BMC Pharmacology . 6 . 3 . January 2006 . 16433932 . 1403760 . 10.1186/1471-2210-6-3 . free .
  5. Shannon HE . Pharmacological analysis of the phencyclidine-like discriminative stimulus properties of narcotic derivatives in rats . The Journal of Pharmacology and Experimental Therapeutics . 222 . 1 . 146–51 . July 1982 . 7086696 .
  6. Slifer BL, Balster RL, May EL . Reinforcing and phencyclidine-like stimulus properties of enantiomers of metazocine . Pharmacology, Biochemistry, and Behavior . 25 . 4 . 785–9 . October 1986 . 3786338 . 10.1016/0091-3057(86)90388-6 . 32126170 .
  7. Web site: Quotas - 2014 . Diversion Control Division . U.S. Department of Justice, Drug Enforcement Administration .
  8. 10.1021/jo01362a017. Structures Related to Morphine. VIII. Further Syntheses in the Benzomorphan Series*1,2. The Journal of Organic Chemistry. 22. 11. 1366–1369. 1957. May EL, Fry EM .
  9. 10.1021/jo01092a011. Structures Related to Morphine. XI.1Analogs and a Diastereoisomer of 2'-Hydroxy-2,5,9-trimethyl-6,7-benzomorphan. The Journal of Organic Chemistry. 24. 10. 1432–1435. 1959. May EL, Ager JH .
  10. Singh, Kamal Nain; Singh, Pushpinder; Sharma, Arvind Kumar; Singh, Paramjit; Kessar, Satinder V. (2010). "A Short Synthesis of Benzomorphane Analgesics (±)-Metazocine and (±)-Phenazocine". Synthetic Communications. 40 (24): 3716–3720. doi:10.1080/00397910903531722.

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