Novel oxotremorine-related heterocyclic derivatives: Synthesis and in vitro pharmacology at the muscarinic receptor subtypes

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.

A series of nonquaternized and quaternized butynyl derivatives related to Oxotremorine was synthesized, and tested at muscarinic receptor subtypes (mAChRs).Figure optionsDownload as PowerPoint slide