Synthesis and biological activity of 1,2,4-oxadiazole derivatives: highly potent and efficacious agonists for cortical muscarinic receptors

Abstract

The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head.group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pKa below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.

A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors

“…All other compounds were obtained from Sigma (Dorset). The detailed synthesis of the novel compounds reported here is published elsewhere Street et al, 1990). …”

Reductive Cleavage of Potential Cholinomimetics Thiadiazolidinones: A New Family of Spiro Compounds

“…[11] The IC 50 values were determined from displacement curves. The values here are reported as means ± SEM of three independent experiments.…”

Synthesis and Potential Muscarinic Receptor Binding and Antioxidant Properties of 3-(Thiadiazolyl)pyridine 1-Oxide Compounds

“…[16] The IC50 values were determined from Hill plots of the inhibition data. The values are here reported as means ± SEM of three independent experiments each performed in triplicate.…”