Binding profiles of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m(1)-m(5)) and their relationship to nootropic activity

The muscarinic binding profile of a series of 2-arylpropionic acid esters o n cloned human muscarinic receptor subtypes (m(1)-m(5)) was determined to i nvestigate 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 them and m(4) receptors. Compounds 1, 7 and 9 show good affinity for m4 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 mu g kg(-1) i .p.) and 7 (1-10 mu g kg(-1) i.p.), injected 20 min before the training ses sion, 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 motili ty as evaluated by the rota-rod test and Animex apparatus experiments.