Interactions of cocaine with primary and secondary recognition sites on muscarinic receptors - PubMed (original) (raw)
Affiliations
- PMID: 1569924
Interactions of cocaine with primary and secondary recognition sites on muscarinic receptors
D D Flynn et al. Mol Pharmacol. 1992 Apr.
Abstract
Several lines of evidence have suggested that muscarinic receptors may possess more than one ligand binding site. In this study, the interactions of cocaine with primary and secondary (allosteric) sites on muscarinic receptors in membrane homogenates from post-mortem human brainstem were examined. (-)-Cocaine inhibited the binding of the tritiated muscarinic antagonists N-methylscopolamine (NMS) and pirenzepine to an apparent single class of sites, with Ki values of 200-300 microM. The binding of the muscarinic agonist [3H]oxotremorine-M was inhibited with a similar Ki value (200 microM). (+)-Cocaine, although not the naturally occurring stereoisomer, was 10-20-fold more potent than (-)-cocaine in competing for binding to the primary muscarinic recognition site. The binding of cocaine was unaffected by guanine nucleotides or N-ethylmaleimide, consistent with its purported action as a competitive antagonist. Cocaine was not selective for muscarinic receptor subtypes. Rosenthal analysis of the [3H]NMS saturation binding data in the presence of increasing concentrations of either (-)-cocaine or (+)-cocaine indicated that both isomers produced an apparent competitive-like reduction in the [3H]NMS affinity. Schild regression analysis of the saturation binding data resulted in curvilinear plots suggestive of cooperative or allosteric interactions of (-)-cocaine with the [3H]NMS-labeled receptors. The effects of (-)-cocaine on the kinetics of [3H]NMS binding were consistent with an allosteric interaction with the receptor. Increasing concentrations of cocaine markedly slowed the rate of [3H]NMS dissociation from the primary recognition site. The allosteric modulation of [3H] NMS binding by (-)-cocaine was abolished with increasing ionic strength. Taken together, these data demonstrate that (-)-cocaine interacts with primary and allosteric recognition sites on muscarinic receptors.
Similar articles
- Selectivity of class I antiarrhythmic agents, disopyramide, pirmenol, and pentisomide for peripheral muscarinic M2 and M3 receptors.
Endou M, Hattori Y, Gando S, Kanno M. Endou M, et al. J Cardiovasc Pharmacol. 1992 May;19(5):674-81. J Cardiovasc Pharmacol. 1992. PMID: 1381764 - Allosteric regulation of muscarinic receptors.
Birdsall NJ, Lazareno S, Matsui H. Birdsall NJ, et al. Prog Brain Res. 1996;109:147-51. doi: 10.1016/s0079-6123(08)62096-8. Prog Brain Res. 1996. PMID: 9009701 Review. No abstract available. - Multiple allosteric sites on muscarinic receptors.
Birdsall NJ, Lazareno S, Popham A, Saldanha J. Birdsall NJ, et al. Life Sci. 2001 Apr 27;68(22-23):2517-24. doi: 10.1016/s0024-3205(01)01047-5. Life Sci. 2001. PMID: 11392621 Review.
Cited by
- The role of acetylcholine in cocaine addiction.
Williams MJ, Adinoff B. Williams MJ, et al. Neuropsychopharmacology. 2008 Jul;33(8):1779-97. doi: 10.1038/sj.npp.1301585. Epub 2007 Oct 10. Neuropsychopharmacology. 2008. PMID: 17928814 Free PMC article. Review. - Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens.
Grimm U, Fuder H, Moser U, Bümert HG, Mutschler E, Lambrecht G. Grimm U, et al. Naunyn Schmiedebergs Arch Pharmacol. 1994 Jan;349(1):1-10. doi: 10.1007/BF00178199. Naunyn Schmiedebergs Arch Pharmacol. 1994. PMID: 8139696 - Mechanisms of acute cocaine toxicity.
Heard K, Palmer R, Zahniser NR. Heard K, et al. Open Pharmacol J. 2008;2(9):70-78. doi: 10.2174/1874143600802010070. Open Pharmacol J. 2008. PMID: 19568322 Free PMC article. - Altered neural cholinergic receptor systems in cocaine-addicted subjects.
Adinoff B, Devous MD Sr, Williams MJ, Best SE, Harris TS, Minhajuddin A, Zielinski T, Cullum M. Adinoff B, et al. Neuropsychopharmacology. 2010 Jun;35(7):1485-99. doi: 10.1038/npp.2010.18. Epub 2010 Mar 10. Neuropsychopharmacology. 2010. PMID: 20393457 Free PMC article. - Evidence for cocaine and methylecgonidine stimulation of M(2) muscarinic receptors in cultured human embryonic lung cells.
Yang Y, Ke Q, Cai J, Xiao YF, Morgan JP. Yang Y, et al. Br J Pharmacol. 2001 Jan;132(2):451-60. doi: 10.1038/sj.bjp.0703819. Br J Pharmacol. 2001. PMID: 11159694 Free PMC article.