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6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode

6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode
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.
human, quantitative structure-activity relationship, cho cells, receptors, transfection, metabolism, chemistry, antagonists & inhibitors, radioligand assay, somatostatin, protein, stereoisomerism
0022-2623
5684-5697
Ulven, Trond
32967da2-8062-44a2-ae6b-736f2990d888
Frimurer, Thomas M.
0feaadde-0043-4331-bb9e-8526d3d8d92d
Receveur, Jean-Marie
5a5749fc-9759-4c44-a2b9-94cfedc87301
Little, Paul Brian
1bf2d1f7-200c-47a5-ab16-fe5a8756a777
Rist, Øystein
25d7e6ac-1308-4edd-ae0b-9a66ecaf741d
Norregaard, Pia K.
f5f89b61-8084-45e1-a2ec-b73eb087186f
Hogberg, Thomas
8ce1581b-db74-476b-9f19-f5da6702ec7a
Ulven, Trond
32967da2-8062-44a2-ae6b-736f2990d888
Frimurer, Thomas M.
0feaadde-0043-4331-bb9e-8526d3d8d92d
Receveur, Jean-Marie
5a5749fc-9759-4c44-a2b9-94cfedc87301
Little, Paul Brian
1bf2d1f7-200c-47a5-ab16-fe5a8756a777
Rist, Øystein
25d7e6ac-1308-4edd-ae0b-9a66ecaf741d
Norregaard, Pia K.
f5f89b61-8084-45e1-a2ec-b73eb087186f
Hogberg, Thomas
8ce1581b-db74-476b-9f19-f5da6702ec7a

Ulven, Trond, Frimurer, Thomas M., Receveur, Jean-Marie, Little, Paul Brian, Rist, Øystein, Norregaard, Pia K. and Hogberg, Thomas (2005) 6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode. Journal of Medicinal Chemistry, 48 (18), 5684-5697. (doi:10.1021/jm050103y).

Record type: Article

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.

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More information

Published date: 13 August 2005
Keywords: human, quantitative structure-activity relationship, cho cells, receptors, transfection, metabolism, chemistry, antagonists & inhibitors, radioligand assay, somatostatin, protein, stereoisomerism

Identifiers

Local EPrints ID: 62175
URI: https://eprints.soton.ac.uk/id/eprint/62175
ISSN: 0022-2623
PURE UUID: 1a1ad224-8092-411e-9cb5-e6c35601c0a7

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Date deposited: 10 Sep 2008
Last modified: 13 Mar 2019 20:27

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