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Br J Clin Pharmacol. 1979; 7(Suppl 3): 273S–279S.
PMCID: PMC1429308

History and development of mixed opioid agonists, partial agonists and antagonists


1 A brief history of the development of narcotic antagonists is outlined.

2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed.

3 An extension of this theory to a three-receptor model (μ, χ and σ) is required to rationalize the pharmacology of the antagonist analgesics cyclazocine, pentazocine and nalorphine.

4 The methodologies available for the study of compounds with dual agonist-antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the χ-partial agonist, nalorphine and the μ-partial agonist buprenorphine are outlined.

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Selected References

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  • ARCHER S, ALBERTSON NF, HARRIS LS, PIERSON AK, BIRD JG, KEATS AS, TELFORD J, PAPADOPOULOS CN. Narcotic antagonists as analgesics. Science. 1962 Aug 17;137(3529):541–543. [PubMed]
  • Gilbert PE, Martin WR. The effects of morphine and nalorphine-like drugs in the nondependent, morphine-dependent and cyclazocine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976 Jul;198(1):66–82. [PubMed]
  • Gilbert PE, Martin WR. Sigma effects of nalorphine in the chronic spinal dog. Drug Alcohol Depend. 1976 Oct;1(6):373–376. [PubMed]
  • ISBELL H, FRASER HF. Addiction to analgesics and barbiturates. J Pharmacol Exp Ther. 1950 Aug;99(42):355–397. [PubMed]
  • Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther. 1967 Aug;157(2):420–426. [PubMed]
  • Jasinski DR, Martin WR, Sapira JD. Antagonism of the subjective, behavioral, pupillary, and respiratory depressant effects of cyclazocine by naloxone. Clin Pharmacol Ther. 1968 Mar-Apr;9(2):215–222. [PubMed]
  • Jasinski DR, Martin WR, Hoeldtke RD. Effects of short- and long-term administration of pentazocine in man. Clin Pharmacol Ther. 1970 May-Jun;11(3):385–403. [PubMed]
  • Keats AS, Telford J. Studies of analgesic drugs. X. Respiratory effects of narcotic antagonists. J Pharmacol Exp Ther. 1966 Jan;151(1):126–132. [PubMed]
  • LASAGNA L, BEECHER HK. The analgesic effectiveness of codeine and meperidine (demerol). J Pharmacol Exp Ther. 1954 Nov;112(3):306–311. [PubMed]
  • Martin WR. Opioid antagonists. Pharmacol Rev. 1967 Dec;19(4):463–521. [PubMed]
  • Martin WR. Pharmacological redundancy as an adaptive mechanism in the central nervous system. Fed Proc. 1970 Jan-Feb;29(1):13–18. [PubMed]
  • Martin WR, Fraser HF, Gorodetzky CW, Rosenberg DE. Studies of the dependence-producing potential of the narcotic antagonist 2-cyclopropylmethyl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphan (cyclazocine, WIN-20,740, ARC II-c-3). J Pharmacol Exp Ther. 1965 Dec;150(3):426–436. [PubMed]
  • Martin WR, Gorodetzky CW. Demonstration of tolerance to and physical dependence of N-allylnormorphine (nalorphine). J Pharmacol Exp Ther. 1965 Dec;150(3):437–442. [PubMed]
  • McClane TK, Martin WR. Effects of morphine, nalorphine, cyclazocine, and naloxone on the flexor reflex. Int J Neuropharmacol. 1967 Mar;6(2):89–98. [PubMed]
  • McClane TK, Martin WR. Antagonism of the spinal cord effects of morphine and cyclazocine by naloxone and thebaine. Int J Neuropharmacol. 1967 Jul;6(4):325–327. [PubMed]
  • WIKLER A, FRASER HF, ISBELL H. N-Allylnormorphine: effects of single doses and precipitation of acute abstinence syndromes during addiction to morphine; methadone or heroin in man (post addicts). J Pharmacol Exp Ther. 1953 Sep;109(1):8–20. [PubMed]

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