Selective agents for muscarinic receptors linked to phosphoinositide breakdown

We examined the effects of several muscarinic agonists and antagonists on phosphoinositide breakdown (PI) and adenylate cyclase (AC) inhibition in rat cerebral cortex and heart, respectively. Acetylcholine, carbachol and methacholine behaved as full agonists in both systems. In contrast, oxotremorine and arecoline failed to stimulate PI turnover but were potent and efficacious at inhibiting AC. Among the antagonists, pirenzepine, dicyclomine, telenzepine and (R)-QNA were both potent (K_i ∼ 0.5-7.5 nM) and selective (90- to 8 500-fold) for the PI-linked (putatively M₁) brain receptor. In contrast, the cardioselective and ileal-selective M₂ antagonists, AF-DX 116 and hexahydrosiladifenidol, were equipotent, competitive inhibitors of both responses. The selectivity of these drugs in terms of their biochemical responses is described.