Synthesis and pharmacological characterization of O-alkynyloximes of tropinone and N-methylpiperidinone as muscarinic agonists.
A number of O-alkynyloximes of tropinone and N-methyl-4-piperidinone have been synthesized and evaluated for muscarinic activity. The affinities of these oximes were tested in homogenates of cerebral cortex, heart, and submandibulary glands from rats using [3H]pirenzepine and [3H]-N-methylscopolamine as radioligands. The oximes bind to the cortical muscarinic receptors with pKi values varying from 3 to 7. Higher binding affinities were observed for the O-alkynyl tropinone oximes than the corresponding piperidinone analogues. Binding to the muscarinic sites in the heart and submandibulary glands was also observed but with lower affinities. Good M1 subtype selectivity (10-fold or greater) was observed with some oximes (26a, 28a, 32a) at the cortical sites. These oximes also attenuated scopolamine-induced impairment of the water mask task in mice. Functional assays for M3 activity on the rat aorta showed that all oximes possessed M3 agonist action but M2 agonist activity was not observed at the endothelium-denuded rabbit aorta. Analysis of the quantitative structure-activity relationship (QSAR) indicated that the Connolly surface area is an important determinant of activity, accounting for 70% of the variation in cortical binding affinity among the oximes.
Xu
R
R
Departments of Pharmacy and Pharmacology, National University of Singapore, 10 Kent Ridge Crescent, Republic of Singapore 119260.
Sim
M K
MK
Go
M L
ML
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D015195:Drug Design; D004924:Escape Reaction / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019832:N-Methylscopolamine / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010890:Pirenzepine / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D018721:Muscarinic Agonists; D010880:Piperidines; D011976:Receptors, Muscarinic; D014326:Tropanes; D010890:Pirenzepine; C016808:3-tropinone; D019832:N-Methylscopolamine