Identification and characterization of m1 selective muscarinic receptor antagonists

A series of esters of 1,4-disubstituted tetrahydropyridine carboxylic acids (I) has been synthesized and characterized as potential mi selective musca rinic receptor antagonists. The affinity of these compounds for the five hu man muscarinic receptor subtypes (Hm1-Hm5) was determined by the displaceme nt of [H-3]-NMS binding using membranes from transfected Chinese hamster ov arian cells. One of the most potent and selective compounds of this series is an analogue of I [11, R-1 = (CH2)(5)CH3], which has an IC50 value of 27. 3 nM at the m1 receptor and possesses 100-fold (m2), 48-fold (m3), 74-fold (m4), and 19-fold (m5) selectivities at the other receptors. Thus, this ana logue appears to be more selective on the basis of binding than the prototy pical mi antagonist, pirenzepine. Functional data, such as the inhibition o f carbachol-stimulated phosphatidylinositol hydrolysis, on selected analogu es confirmed the muscarinic antagonistic properties of this chemical series .