High-throughput screening of novel antagonists on melanin-concentrating hormone receptor-11
Jian-hua YAN
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorQun-yi LI
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorJean A BOUTIN
Les Laboratoires Servier, Neuilly-sur-Seine 92200, France
Search for more papers by this authorM Pierre RENARD
Les Laboratoires Servier, Neuilly-sur-Seine 92200, France
Search for more papers by this authorYi-xiang DING
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Search for more papers by this authorXiao-jiang HAO
Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
Search for more papers by this authorWei-min ZHAO
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorCorresponding Author
Ming-wei WANG
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to Dr Ming-wei WANG. Phn 86-21-5080-1313. Fax 86-21-5080-0721. E-mail [email protected]Search for more papers by this authorJian-hua YAN
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorQun-yi LI
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorJean A BOUTIN
Les Laboratoires Servier, Neuilly-sur-Seine 92200, France
Search for more papers by this authorM Pierre RENARD
Les Laboratoires Servier, Neuilly-sur-Seine 92200, France
Search for more papers by this authorYi-xiang DING
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Search for more papers by this authorXiao-jiang HAO
Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China
Search for more papers by this authorWei-min ZHAO
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Search for more papers by this authorCorresponding Author
Ming-wei WANG
The National Center for Drug Screening and the State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Correspondence to Dr Ming-wei WANG. Phn 86-21-5080-1313. Fax 86-21-5080-0721. E-mail [email protected]Search for more papers by this authorProject supported in part by the Shanghai Municipality Science and Technology Development Fund (No 06DZ22907 and 07DZ22920), the Ministry of Science and Technology (No 2004CB518902), and Servier Beijing Pharmaceutical Research and Development Co, Ltd.
Abstract
Aim: To find new antagonists on human melanin-concentrating hormone recep-tor-1 (MCHR-1) through high-throughput screening (HTS) of a diverse compound library. Methods: MCHR-1, [3H]SNAP7941, and FlashBlue G-protein-coupled receptor beads were used to measure the receptor-binding activities of various compounds based on scintillation proximity assay (SPA) technology. The guanosine 5′ (γ-[35S]thio) triphosphate ([35S]GTPγS) binding assay was subsequently applied to functionally characterize the “hits” identified by the HTS campaign. Results: Of the 48 240 compounds screened with the SPA method, 12 hits were confirmed to possess MCHR-1 binding activities, 8 were functionally studied subsequently with the [35S]GTPγS binding assay, and only 1 compound (NC127816) displayed moderate human MCHR-1 binding affinity (Ki=115.7 nmol/L) and relatively potent antagonism (KB=23.8 nmol/L). This compound shares a novel scaffold (1-ethoxy-2H-2-aza-1-phospha-naphthalene 1-oxide) with 3 other analogs in the group. Conclusion: Considering the marked difference in molecular shape and electrostatic status between NC127816 and the structures reported elsewhere, we anticipate that its derivatives may represent a new class of potent MCHR-1 modulators.
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