Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139.
GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acidsL-Trp andL-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mohamed A
MA
Shehata
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Anne C
AC
Nøhr
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Delphine
D
Lissa
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Christoph
C
Bisig
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Vignir
V
Isberg
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.|Department of Neurodegeneration 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
Kirsten B
KB
Andersen
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Kasper
K
Harpsøe
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Fredrik
F
Björkling
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Hans
H
Bräuner-Osborne
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
David E
DE
Gloriam
D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D006834:Hydrazines / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*
C501535:GPR139 protein, human; D006834:Hydrazines; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D014227:Triazines