piperidines and 3-tropinone

The synthesis of O-propynyloximes of N-methylpiperidinone, 3-tropinone, and 3-quinuclidinone, containing several pyrazole frameworks is described, together with their muscarinic receptor affinities. Compounds derived from N-methylpiperidinone or 3-tropinone and N-(4-methoxybenzyl)- or N-(2,4,6-trimethylbenzoyl)pyrazole showed moderate activity for muscarinic receptors in the rat central nervous system. A semi-empirical AM1 calculation has shown that the O-[(benzoyl-pyrazolyl)propynyl]-oximes of tropinone fit a previously described muscarinic pharmacophoric model, revealing structural features useful for the development of new muscarinic agents.

Topics: Animals; Isomerism; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Muscarinic Agonists; Oximes; Piperidines; Pyrazoles; Quinuclidines; Radioligand Assay; Rats; Receptors, Muscarinic; Structure-Activity Relationship; Tropanes

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.

Topics: Animals; Aorta; Binding, Competitive; Drug Design; Escape Reaction; In Vitro Techniques; Male; Maze Learning; Mice; Models, Molecular; Molecular Structure; Muscarinic Agonists; Muscle Contraction; Muscle, Smooth, Vascular; N-Methylscopolamine; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Pirenzepine; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Structure-Activity Relationship; Tropanes

Topics: Ethers; Heterocyclic Compounds; Piperidines; Piperidones; Tropanes

Topics: Alkaloids; Humans; Mimosine; Piperidines; Pyridines; Tropanes; Yohimbine