Skip to main content
Log in

The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Four groups of narcotic analgesic drugs have been assessed for their opiate activities by using three binding assays and three pharmacological bioassays. In the binding assays, their inhibition constants (K I, nM) were determined against the binding of the μ-ligand, [3H]-[d-Ala 2,MePhe 4, Gly-ol5]enkephalin, of the δ-ligand, [3H]-[d-Ala 2,d-Leu 5]enkephalin and of the ϰ-ligand, [3H]-(±)-ethylketazocine after suppression of μ- and δ-binding by 100 nM of the unlabelled μ-ligand and 100 nM of the unlabelled δ-ligand. The pharmacological agonist or antagonist activities were assayed on the guinea-pig ileum, mouse vas deferens and rat vas deferens.

The first group of compounds were pure agonists in all three pharmacological bioassays. The majority of the compounds showed preference to μ-binding but phenazocine and particularly etorphine had also high affinities to the δ- and ϰ-binding sites.

The second group consisted of N-allyl and N-cyclopropylmethyl homologues of the morphine, 3-hydroxymorphinan and normetazocine series which had agonist and antagonist activities in the guinea-pig ileum and mouse vas deferens but were pure antagonists in the rat vas deferens. In the binding assays, μ-binding and ϰ-binding were prominent.

The third group was made up by the ketazocine-like compounds which in the guinea-pig ileum and mouse vas deferens were pure agonists and in the rat vas deferens pure antagonists. The binding spectrum showed particularly high binding to the ϰ-binding site.

The fourth group was the antagonists which were devoid of agonist activity with the exception of diprenorphine and Mr 2266 which had retained some agonism. The binding spectrum showed considerable variation, naloxone in low concentration being a selective μ-antagonist, Mr 2266 having high affinities to the μ- and ϰ-binding sites and diprenorphine having considerable affinities to the μ-, δ- and ϰ-binding sites.

Since each of the four groups of compounds, whether pure agonists, agonist-antagonists, ketazocine-like drugs or pure antagonists, shows independent varittions in the affinities to the μ- and ϰ-binding sites, their different pharmacological behaviour cannot be solely due to difference in the binding spectra.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adler MW (1981) Mini symposium II. The in vivo differentiation of opiate receptors: Introduction. Life Sci 28:1543–1545

    Google Scholar 

  • Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58

    Google Scholar 

  • Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the ϰ opioid receptor. Science 215:413–415

    Google Scholar 

  • Cheng Y-C, Prusoff WH (1973) Relationship between the inhibition constant (K I) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22: 309–3102

    Google Scholar 

  • Cowan A (1981) Mini symposium III. Simple in vivo tests that differentiate prototype agonists at opiate receptors. Life Sci 28:1559–1570

    Google Scholar 

  • Gilbert PE, Martin WR (1976) The effects of morphine-and nalorphinelike drugs in the nondependent and morphine-dependent and cyclazocine-dependent chronic spinal dog. J Pharmacol Exp Ther 198: 66–82

    Google Scholar 

  • Gillan MGC, Kosterlitz HW, Magnan J (1981) Unexpected antagonism in the rat vas deferens by benzomorphans which are agonists in other pharmacological tests. Br J Pharmacol 72:13–15

    Google Scholar 

  • Gillan MGC, Kosterlitz HW, Paterson SJ (1980) Comparison of the binding characteristics of tritiated opiates and opioid peptides. Br J Pharmacol 70:481–490

    Google Scholar 

  • Herling S, Woods JH (1981) Mini symposium IV. Discriminative stimulus effects of narcotics: evidence for multiple receptor-mediated actions. Life Sci 28:1571–1584

    Google Scholar 

  • Hughes J, Kosterlitz HW, Leslie FM (1975) Effect of morphine on adrenergic transmission in the mouse vas deferens. Assessment of agonist and antagonist potencies of narcotic analgesics. Br J Pharmacol 53:371–381

    Google Scholar 

  • Hutchinson M, Kosterlitz HW, Leslie FM, Waterfield AA, Terenius L (1975) Assessment in the guinea-pig ileum and mouse vas deferens of benzomorphans which have strong antinociceptive activity but do not substitute for morphine in the dependent monkey. Br J Pharmacol 55:541–546

    Google Scholar 

  • Kosterlitz HW, Watt AJ (1968) Kinetic parameters of narcotic agonists and antagonists, with particular reference to N-allylnoroxymorphone (naloxone). Br J Pharmacol 33:266–276

    Google Scholar 

  • Kosterlitz HW, Lord JAH (1971) The morphine receptor in the guineapig ileum. Bull Probl Drug Dependence 33:532–544

    Google Scholar 

  • Kosterlitz HW, Waterfield AA (1975) In vitro models in the study of structure-activity relationships of narcotic analgesics. Ann Rev Pharmacol 15:29–57

    Google Scholar 

  • Kosterlitz HW, Paterson SJ (1980) Characterization of opioid receptors in nervous tissues. Proc R Soc B 210:113–122

    Google Scholar 

  • Kosterlitz HW, Paterson SJ (1981) Tyr-d-Ala-Gly-MePhe-Gly-ol is a selective ligand for the μ-opiate binding site. Br J Pharmacol 73: 299P

  • Kosterlitz HW, Hughes J, Leslie FM, Lord JAH, Waterfield AA (1977) Evidence at the cellular level for the presence of several opiate receptors. Bull Probl Drug Dependence 39:121–132

    Google Scholar 

  • Kosterlitz HW, Leslie FM, Waterfield AA (1975) Rates of onset and offset of action of narcotic analgesics in isolated preparations. Eur J Pharmacol 32:10–16

    Google Scholar 

  • Kosterlitz HW, Lord JAH, Paterson SJ, Waterfield AA (1980) Effects of changes in the structure of enkephalins and of narcotic analgesic drugs on their interactions with μ- and δ-receptors. Br J Pharmacol 68:333–342

    Google Scholar 

  • Kosterlitz HW, Lord JAH, Watt AJ (1972) Morphine receptor in the myenteric plexus of the guinea-pig ileum. In: Kosterlitz HW, Collier HOJ, Villarreal JE (eds) Agonist and antagonist actions of narcotic analgesic drugs. Macmillan, London, pp 45–61

    Google Scholar 

  • Kosterlitz HW, Lydon RJ, Watt AJ (1970) The effects of adrenaline, noradrenaline and isoprenaline on inhibitory α- and β-adrenoceptors in the longitudinal muscle of the guinea-pig ileum. Br J Pharmacol 39:398–413

    Google Scholar 

  • Kosterlitz HW, Magnan J, Paterson SJ, Tavani A (1981) Activity profiles of opiates at the μ-, δ- and ϰ-binding sites. Br J Pharmacol 74: 893P

  • Kosterlitz HW, Paterson SJ, Robson LE (1981) Characterization of the ϰ-subtype of the opiate receptor in the guinea-pig brain. Br J Pharmacol 73:939–949

    Google Scholar 

  • Kosterlitz HW, Waterfield AA, Berthoud V (1973) Assessment of the agonist and antagonist properties of narcotic analgesic drugs by their actions on the morphine receptor in the guinea-pig ileum. In: Braude MC, Harris LS, May EL, Smith JP, Villarreal JE (eds) Narcotic antagonists. Advances in biochemical psychopharmacology, vol 8. Raven Press, New York, pp 319–334

    Google Scholar 

  • Kosterlitz HW, Waterfield AA, Berthoud V (1974) The assessment of agonist and antagonist properties of narcotic analgesic drugs by their actions on the morphine receptor in the guinea-pig ileum. Bull Probl Drug Dependence 36:56–65

    Google Scholar 

  • Lemaire S, Magnan J, Regoli D (1978) Rat vas deferens: a specific bioassay for endogenous opioid peptides. Br J Pharmacol 64:327–329

    Google Scholar 

  • Lord JAH, Waterfield AA, Hughes J, Kosterlitz HW (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267:495–499

    Google Scholar 

  • Martin WR (1967) Opioid antagonists. Pharmacol Rev 19:463–521

    Google Scholar 

  • Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532

    Google Scholar 

  • Martin WR, Eades CG, Gilbert PE, Thompson JA (1980) Tolerance to and physical dependence on N-allylnormetazocine (NANM) in chronic spinal dogs. Subst Alcohol Actions/Misuse 1:269–279

    Google Scholar 

  • Osei-Gyimah P, Archer S, Gillan MGC, Kosterlitz HW (1981) Some 14β-substituted analogue of N(cyclopropylamethyl)normorphine. J Med Chem 24:212–214

    Google Scholar 

  • Pfeiffer A, Pasi A, Mehraein P, Herz A (1981) A subclassification of ϰ-sites in the human brain by use of dynorphin 1–17. Neuropeptides 2:89–97

    Google Scholar 

  • Quirion R, Hammer Jr RP, Herkenham M, Pert CB (1981) Phenylcyclidine (angle dust)/σ “opiate” receptor: visualization by tritiumsensitive film. Proc Natl Acad Sci USA 78:5881–5885

    Google Scholar 

  • Su T-P (1981) Psychomimetic opioid binding: specific binding of [3H] SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. Eur J Pharmacol 75:81–82

    Google Scholar 

  • Swain HH, Seevers MH (1974) Evaluation of new compounds for morphine-like physical dependence in the rhesus monkey. Bull Probl Drug Dependence 36: Addendum 1168-1195

    Google Scholar 

  • Swain HH, Seevers MH (1976) Evaluation of new compounds for morphine-like physical dependence in the rhesus monkey. Bull Probl Drug Dependence 38: Addendum 2, 768–787

    Google Scholar 

  • Villarreal JE, Seevers MH (1972) Evaluation of new compounds for morphine-like physical dependence in the rhesus monkey. Bull Probl Drug Dependence 34: Addendum 7, 1040–1053

    Google Scholar 

  • Waterfield AA, Kosterlitz HW (1975) Stereospecific increase by narcotic antagonists of evoked acetylcholine output in guinea-pig ileum. Life Sci 16:1787–1792

    Google Scholar 

  • Waterfield AA, Smokcum RWJ, Hughes J, Kosterlitz HW, Henderson G (1977) In vitro pharmacology of the opioid peptides, enkephalins and endorphins. Eur J Pharmacol 43:107–116

    Google Scholar 

  • Wolozin BL, Pasternak GW (1981) Classification of multiple morphine and enkephalin binding sites in the central nervous system. Proc Natl Acad Sci USA 78:6181–6185

    Google Scholar 

  • Wüster M, Herz A (1976) Significance of physio-chemical properties of opiates for in vitro testing. In: Kosterlitz HW (ed) Opiates and endogenous opioid peptides. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 447–450

    Google Scholar 

  • Wüster M, Rubini P, Schulz R (1981) The preference of putative proenkephalins for different types of opiate receptors. Life Sci 29:1219–1227

    Google Scholar 

  • Wüster M, Schulz R, Herz A (1980) Opioid agonists and antagonists: Action on multiple opiate receptors. In: Way EL (ed) Endogenous and exogenous opiate agonists and antagonists. Pergamon Press, New York, pp 75–78

    Google Scholar 

  • Zhang AZ, Paternak GW (1981) Opiates and enkephalins: a common binding site mediates their analgesic actions in rats. Life Sci 29: 843–851

    Google Scholar 

  • Zukin RS, Zukin SR (1981) Demonstration of [3H] cyclazocine to multiple opiate receptor sites. Mol Pharmacol 20:246–254

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Magnan, J., Paterson, S.J., Tavani, A. et al. The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn-Schmiedeberg's Arch. Pharmacol. 319, 197–205 (1982). https://doi.org/10.1007/BF00495865

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00495865

Key words

Navigation