New opiate-receptor model.

Abstract

A new opiate-receptor model is proposed in which only one conformation of the receptor is needed for binding of both agonists and antagonists. There are two different spacially fixed amine-binding sites in this model: one agonist and one antagonist. The opiates undergo binding to their amine-binding sites via the lone electron pair on nitrogen. The role of the N-allyl or other such group in imparting antagonist properties is explained in terms of the steric requirements of this group. For this group to be accommodated without imposing severe steric interactions in the rest of the opiate molecule, the piperidine ring must assume a flexible (skew boat) conformation; in this conformation, the N-lone-pair electron lobe assumes the characteristic directionality of an antagonist toward its amine-binding site. If the N-lone-pair lobe is not rigorously maintained in this direction, the opiate molecule assumes both antagonist and agonist conformations and mixed antagonist-agonist activity is observed. The observed differences in the effect of sodium on the degree of binding of an agonist versus an antagonist can be explained in this model by the different effects of sodium on the two amine-binding sites. The antagonist activity of an N-methyl antagonist can be rationalized on the basis of the proposed model.