1,2,5-Thiadiazole derivatives of arecoline stimulate M1 receptors coupled to phosphoinositide turnover.

Abstract A series of alkoxy-1,2,5-thiadiazole derivatives of arecoline was synthesized in an effort develop M 1 muscarinic agonists. The 3-butenyloxy, 2-butynyloxy, cyclopropylmethyloxy, and hexyloxy derivatives stimulated phosphoinositide turnover through muscarinic receptors in the rat hippocampus. The dose-response curves of 2-butynyloxy, cyclopropylmethyloxy and hexyloxy compounds were found to be biphasic compared to arecoline. The maximal PI turnover response of arecoline and the hexyloxy compound together was the same as the response of each separately. Pirenzepine was somewhat more potent than AF-DX 116 for inhibiting the responses produced by low concentrations of the thiadiazole derivatives. The data suggest that the cyclopropylmethyloxy-TZTP derivative is functionally a selective M 1 agonist. Molecular mechanics calculations indicate that the anti form of the 1,2,5-thiadiazole derivatives of arecoline may be active at M 1 receptors.