Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139

Vignir Isberg; Kirsten B Andersen; Christoph Bisig; Gunnar P H Dietz; Hans Bräuner-Osborne; David E Gloriam

doi:10.1021/ci500197a

Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139

J Chem Inf Model. 2014 Jun 23;54(6):1553-7. doi: 10.1021/ci500197a. Epub 2014 May 30.

Authors

Vignir Isberg¹, Kirsten B Andersen, Christoph Bisig, Gunnar P H Dietz, Hans Bräuner-Osborne, David E Gloriam

Affiliation

¹ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.

PMID: 24826842
DOI: 10.1021/ci500197a

Abstract

GPR139 is an orphan G protein-coupled receptor expressed mainly in the central nervous system. We developed a pharmacophore model based on known GPR139 surrogate agonists which led us to propose aromatic-containing dipeptides as potential ligands. Upon testing, the dipeptides demonstrated agonism in the Gq pathway. Next, in testing all 20 proteinogenic l-α-amino acids, L-tryptophan and l-phenylalanine were found to have EC50 values of 220 and 320 μM, respectively, making them the first putative endogenous agonists for GPR139.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids, Aromatic / chemistry*
Amino Acids, Aromatic / pharmacology*
Computer-Aided Design
Dipeptides / chemistry*
Dipeptides / pharmacology*
Drug Design*
HEK293 Cells
Humans
Models, Molecular
Nerve Tissue Proteins / agonists*
Nerve Tissue Proteins / metabolism
Phenylalanine / chemistry
Phenylalanine / pharmacology
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / metabolism
Tryptophan / chemistry
Tryptophan / pharmacology

Substances

Amino Acids, Aromatic
Dipeptides
GPR139 protein, human
Nerve Tissue Proteins
Receptors, G-Protein-Coupled
Phenylalanine
Tryptophan