The design of full agonists for the cortical muscarinic receptor

In the present study we describe a novel series of oxadiazole based tertiary amines which include the most efficacious and potent muscarinic ligands known. These compounds possess physicochemical characteristics which enable rapid equilibration into the CNS and are able to fully activate cortical muscarinic receptors. Data obtained from this series have allowed us to propose a pharmacophoric model which distinguishes high and low affinity state binding. This in turn has led us to suggest that agonists and antagonists may bind at two independent sites on the receptor protein and to speculate on the steps putatively involved in agonist-induced receptor activation.