Binding profiles of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m1-m5) and their relationship to nootropic activity.

The muscarinic binding profile of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m 1 -m 5 ) was determined to investigate whether there is a correlation between pharmacological activity and muscarinic receptor subtype selectivity. Among the tested compounds. 1, 7 and 9 showed the highest affinity for the m 2 and m 4 receptors. Compounds 1, 7 and 9 show good affinity for m 4 receptors (pKi = 7.87; 7.73 and 7.10, respectively) and are able to discriminate 10-60 fold between m 4 /m 1 , m 4 /m 3 , and m 4 /m 5 subtypes. Conversely, these compounds are able only to weakly discriminate between m 4 /m 2 . Compounds 1 (50-300 μg kg -1 i.p.) and 7 (1-10 μg kg -1 i.p.), injected 20 min before the training session, are able to prevent the amnesia induced by dicyclomine (2 mg kg -1 i.p.) in the mouse passive-avoidance test. Compounds 1 and 7, at the highest antiamnesic doses, do not modify motor coordination and spontaneous motility as evaluated by the rota-rod test and Animex apparatus experiments.