title: A new synthetic approach of N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide (JTC-801) and its analogues and their pharmacological evaluation as nociceptin receptor (NOP) antagonists.
abstract: A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affinity. So 3-methyl derivative 4j showed a similar potency compared with the reference 4h while bulky lipophilic or electron withdrawing groups in the same position strongly decreased affinity. Structural and conformational requirements for affinity were outlined by NOE NMR and computational methods and suggestions for a pharmacophore model design were provided.
authors.affiliation: Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. isestili@iss.it
authors.forename: Isabella
authors.initials: I
authors.lastname: Sestili
authors.forename: Anna
authors.initials: A
authors.lastname: Borioni
authors.forename: Carlo
authors.initials: C
authors.lastname: Mustazza
authors.forename: Andrea
authors.initials: A
authors.lastname: Rodomonte
authors.forename: Luciana
authors.initials: L
authors.lastname: Turchetto
authors.forename: Maria
authors.initials: M
authors.lastname: Sbraccia
authors.forename: Daniela
authors.initials: D
authors.lastname: Riitano
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Del Giudice
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002151:Calorimetry; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016015:Logistic Models; D008968:Molecular Conformation; D015394:Molecular Structure; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000378:metabolism; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D019204:GTP-Binding Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C000722283:OPRL1 protein, human