title: 6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode.
abstract: Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.
authors.affiliation: 7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Receveur
authors.forename: Paul Brian
authors.initials: PB
authors.lastname: Little
authors.forename: Oystein
authors.initials: O
authors.lastname: Rist
authors.forename: Pia K
authors.initials: PK
authors.lastname: Nørregaard
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D010716:Phosphatidylinositols / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013237:Stereoisomerism; D014162:Transfection
chemical_list: D000634:Aminoquinolines; C103263:MCHR1 protein, human; D010716:Phosphatidylinositols; D017481:Receptors, Somatostatin