SITE-DIRECTED ALKYLATION OF MULTIPLE OPIOID RECEPTORS .2. PHARMACOLOGICAL SELECTIVITY

Abstract

A site-directed alkylating agent was used to inactivate one or more types of opioid receptor in 2 bioassay preparations in the presence of type-selective ligands as protectors of other opioid receptor types. Since the pharmacological potency of an agonist is decreased when the receptor type through which it acts has been inactivated, the method can be used to characterize the pharmacological selectivity of opioid agonists. All of the smaller opioid products of the enkephalin gene were .delta.-selective in the mouse vas deferens, but BAM-12P, BAM-22P [bovine adrenal medullary enkephalin precursor fragment] and Peptide E were not. In the same tissue, .beta.c-endorphin was not .mu.-selective, but in the guinea pig ileum preparation it evidently combined with .mu. and .kappa. receptors. The presence of functional .epsilon. receptors could not be ruled out. The approach described is applicable to any pharmacologically active receptors of which there are multiple types, and for which site-directed alkylating agents and type-selective protector ligands are available.