A set of novel heterocyclic ligands (6-27) structurally related to Oxotremorine 2 was designed, synthesized and tested at muscarinic receptor subtypes (mAChRs). In the binding experiments at cloned human receptors (hm1-5), compounds 7 and 15 evidenced a remarkable affinity and selectivity for the hm2 subtype. The in vitro functional assays, performed on a selected group of derivatives at M1, M2, and M3 tissue preparations, singled out the 3-butynyloxy-5-methylisoxazole trimethylammonium salt 7 as a potent unselective muscarinic agonist [pEC50: 7.40 (M1), 8.18 (M2), and 8.14 (M3)], whereas its 5-phenyl analogue 12 behaved as a muscarinic antagonist, slightly selective for the M1 subtype [pKB: 6.88 (M1), 5.95 (M2), 5.53 (M3)]. Moreover, the functional data put in evidence that the presence of the piperidine ring may generate a functional selectivity, e.g., an M1 antagonist/M2 partial agonist/M3 full agonist profile (compound 21), at variance with the corresponding quaternary ammonium salt (compound 22) which behaved as a muscarinic agonist at all M1-3 receptors, with an appreciable selectivity for the cardiac M2 receptors.
Novel oxotremorine-related heterocyclic derivatives : synthesis and in vitro pharmacology at the muscarinic receptor subtypes / C. Dallanoce, M. De Amici, E. Barocelli, S. Bertoni, B. L. Roth, P. Ernsberger, C. De Micheli. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 15:24(2007), pp. 7626-7637.
|Titolo:||Novel oxotremorine-related heterocyclic derivatives : synthesis and in vitro pharmacology at the muscarinic receptor subtypes|
DE AMICI, MARCO (Secondo)
DE MICHELI, CARLO (Ultimo)
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bmc.2007.09.003|
|Appare nelle tipologie:||01 - Articolo su periodico|