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 (m1-m5) 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 m2 and m4 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 m4/m1, m4/m3, and m4/m5 subtypes. Conversely, these compounds are able only to weakly discriminate between m4/m2. Compounds 1 (50-300 micrograms kg-1 i.p.) and 7 (1-10 micrograms 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.
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy. ghelard@server1.pharm.unifi.it
C
C
Ghelardini
I
I
Mizuma
F
F
Gualtieri
A
A
Bartolini
N
N
Galeotti
M N
MN
Romanelli
E
E
Teodori
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000378:metabolism* / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011422:Propionates / Q000378:metabolism* / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011994:Recombinant Proteins
D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D011422:Propionates; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins