6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode.
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.
Ulven
Trond
T
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark.
Frimurer
Thomas M
TM
Receveur
Jean-Marie
JM
Little
Paul Brian
PB
Rist
Oystein
O
Nørregaard
Pia K
PK
Högberg
Thomas
T
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
D000634:Aminoquinolines; C103263:MCHR1 protein, human; D010716:Phosphatidylinositols; D017481:Receptors, Somatostatin