Synthesis and in Vitro Characterization of Novel Amino Terminally Modified Oxotremorine Derivatives for Brain Muscarinic Receptors

Article abstract of DOI:10.1021/jm00087a008

A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M₁ and M₂ receptors.One analogue, 3-(2-oxo-1-pyrrolidinyl)-1-<2(R)-pyrrolidinyl>-1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M₁ receptors approximately 3-fold larger than that produced by 1.The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue (3).All three compounds are partial M₁ agonists and full M₂ agonists; however, the profile of 6a in binding studies is significantly different.While 2 and 3 exhibit large M₂ selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.