Aryldiazonium salts as antagonists at cholinergic muscarinic receptors.

Abstract

A series of aryldiazonium salts were synthesized and tested for inhibitory activity on the longitudinal muscle of the guinea pig ileum. The most potent member of the series, benzenediazonium fluoborate (BDF) (at 10−4 M with incubation for 5 min), produced a dose ratio of 600 for acetylcholine (Ach), 58 for cis-2-methyl-4-trimethylammonium methyl-1,3-dioxolane (CD), and 30 for carbamylcholine (Cch). BDF was significantly less effective against histamine-induced responses and was without effect on K+-induced responses. BDF produced a differential effect on muscarinic responses, producing right-ward shifts of dose–response curves of polar ligands but only depressing maximal responses of nonpolar ligands. An exception to this was amyl-trimethylammonium, for which the curves were shifted and the maximal responses depressed. Protection experiments showed that polar ligands (Cch, CD) offered protection against BDF antagonism of nonpolar ligand (alkyl-trimethylammonium) responses that decreased with alkyl chain length, but that nonpolar ligands afforded strong protection for both polar and nonpolar activity that was indpendent of chain length. A discussion of these findings is offered in terms of both the receptor reserve concept and of allosteric mechanisms of antagonist action.