Discovery of Diaryl Imidazolidin-2-one Derivatives, a Novel Class of Muscarinic M3 Selective Antagonists (Part 2)

• Published in: Journal of medicinal chemistry Vol. 50; no. 7; pp. 1693 - 1697
• Main Authors: Peretto, Ilaria, Fossati, Claudia, Giardina, Giuseppe A. M, Giardini, Alessandra, Guala, Matilde, La Porta, Elena, Petrillo, Paola, Radaelli, Stefano, Radice, Luigi, Raveglia, Luca F, Santoro, Enza, Scudellaro, Roberta, Scarpitta, Francesca, Cerri, Alberto, Menegon, Sergio, Dondio, Giulio M, Rizzi, Andrea, Armani, Elisabetta, Amari, Gabriele, Civelli, Maurizio, Villetti, Gino, Patacchini, Riccardo, Bergamaschi, Marco, Bassani, Franco, Delcanale, Maurizio, Imbimbo, Bruno P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 05-04-2007
• Subjects: Animals; Biological and medical sciences; Bronchoconstriction - drug effects; Bronchodilator Agents - chemical synthesis; Bronchodilator Agents - chemistry; Bronchodilator Agents - pharmacology; CHO Cells; Cholinergic system; Cricetinae; Cricetulus; Guinea Pigs; Humans; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; In Vitro Techniques; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Myocardial Contraction - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Quaternary Ammonium Compounds - chemical synthesis; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Radioligand Assay; Receptor, Muscarinic M3 - antagonists & inhibitors; Respiratory system; Structure-Activity Relationship; Trachea - drug effects; Trachea - physiology; Five membered ring; Organic cation; Nitrogen heterocycle; Selectivity; Pyridine derivatives; Thiophene derivatives; Bronchoconstriction; Cholinergic receptor; Guinea pig; Structure activity relation; Ureas; Antagonist; M3 Muscarinic receptor; Bronchodilator; Rodentia; Benzene derivatives; Ketone; In vitro; Quaternary ammonium compound; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Organic fluorine compounds; Affinity; Intratracheal administration
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061160+

Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.