Search for lead structures to develop new allosteric modulators of muscarinic receptors. J Pharmacol Exp Ther 279:926–933

Various compounds are known to allosterically modulate the binding of ligands to muscarinic receptors. Most of these com-pounds have another predominant pharmacological action. Identification of the potent representatives should be useful for the development of allosteric modulators that are specific and highly active. For various reasons, a direct comparison of allo-steric potencies on the basis of literature data is difficult. There-fore, a series of compounds was compared with regard to the allosteric delay of the dissociation of N-[3H]methylscopolamine from porcine heart M2 receptors under the following assay conditions: “Na,K,P buffer”, 4 mM Na2HPO4, 1 mM KH2PO4, pH 7.4, 23#{176}C;“Mg,Tris,Cl,P buffer”, 50 mM Tris-HCI, 3 mM MgHPO4, pH 7.3, 37#{176}C.Generally, the allosteric potency of the compounds was higher in the Na,K,P1 buffer, compared with the Mg,Tris,Cl,P buffer. However, the extent of the potenc