1,2,5-Thiadiazole derivatives of arecoline stimulate M1 receptors coupled to phosphoinositide turnover.
A series of alkoxy-1,2,5-thiadiazole derivatives of arecoline was synthesized in an effort to develop M1 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 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 thiadiazole derivatives. The data suggest that the cyclopropylmethyloxy-TZTP derivative is functionally a selective M1 agonist. Molecular mechanics calculations indicate that the anti form of the 1,2,5-thiadiazole derivatives of arecoline may be active at M1 receptors.
Periyasamy
S
S
Department of Medicinal and Biological Chemistry, University of Toledo, College of Pharmacy, OH 43606, USA.
Messer
W S
WS
Roknich
S
S
Sauerberg
P
P
Hoss
W
W
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D010890:Pirenzepine; D001115:Arecoline; C048593:otenzepad