Pharmacological characterization of the aminopyridazine SR 95639A, a selective M1 muscarinic agonist

Abstract In order to design a selective M 1 muscarinic agonist, we synthesized SR 95639A (morpholinoethylamino-3-benzo-cyclochepta-(5,6-c)-pyridazine, dihydrochloride), a semi-rigid analogue of the aminopyridazine antidepressant drug minaprine. SR 95639A displaced [ 3 H]pirenzepine from its binding sites in rat hippocampal membranes with an IC 50 value of 0.27 μM. It only weakly displaced [ 3 H]N-methylscopolamine from cerebellar, cardiac and ileal membranes (10–48 μM), and, up to 100 μM, did not interact with the main other receptors of the rat brain. In rat isolated sympathetic ganglia, SR 95639A induced dose-dependent depolarizations which were antagonized by pirenzepine, and dose dependently suppressed the M current. These effects were also pirenzepine-sensitive. After i.p. or oral treatment in mice, SR 95639A never induced the classical cholinergic syndrome, up to lethal doses. Finally, SR 95639A (i.p. and p.o.) antagonized contralateral rotations by intrastriatal injection of pirenzepine, in mice. These results suggest that SR 95639A is a selctive agonist at central muscarine M 1 receptors and may represent a useful tool for further characterization of the nature and function of muscarinic receptor subtypes.