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 M(1), M(2), and M(3) tissue preparations, singled out the 3-butynyloxy-5-methylisoxazole trimethylammonium salt 7 as a potent unselective muscarinic agonist [pEC(50): 7.40 (M(1)), 8.18 (M(2)), and 8.14 (M(3))], whereas its 5-phenyl analogue 12 behaved as a muscarinic antagonist, slightly selective for the M(1) subtype [pK(B): 6.88 (M(1)), 5.95 (M(2)), 5.53 (M(3))]. Moreover, the functional data put in evidence that the presence of the piperidine ring may generate a functional selectivity, e.g., an M(1) antagonist/M(2) partial agonist/M(3) full agonist profile (compound 21), at variance with the corresponding quaternary ammonium salt (compound 22) which behaved as a muscarinic agonist at all M(1-3) receptors, with an appreciable selectivity for the cardiac M(2) receptors.
Dallanoce
Clelia
C
Istituto di Chimica Farmaceutica e Tossicologica "Pietro Pratesi", Università degli Studi di Milano, Via Mangiagalli 25, Milano 20133, Italy.
De Amici
Marco
M
Barocelli
Elisabetta
E
Bertoni
Simona
S
Roth
Bryan L
BL
Ernsberger
Paul
P
De Micheli
Carlo
C
D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010095:Oxotremorine / Q000138:chemical synthesis / Q000737:chemistry*; D011817:Rabbits; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000145:classification* / Q000187:drug effects; D011994:Recombinant Proteins / Q000145:classification
D006571:Heterocyclic Compounds; D008024:Ligands; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D010095:Oxotremorine