The G-protein-coupled receptors are a part of the largest and most physiologically relevant family of membrane proteins. One-third of the medications, now on the market, target the GPCR receptor family, which is one of the most important therapeutic targets for many disorders. In the reported work, we have focussed on orphan GPR88 receptor which is a part of the GPCR protein family and a potential target for central nervous system disorders. GPR88 is known to show the highest expression in the striatum, which is a key region in motor control and cognitive functions. Recent studies have reported that GPR88 is activated by two agonists, 2-PCCA and RTI-13951-33. In this study, we have predicted the three-dimensional protein structure for the orphan GPR88 using the homology modeling approach. We then used shape-based screening techniques based on known agonists and structure-based virtual screening methods employing docking to uncover novel GPR88 ligands. The screened GPR88-ligand complexes were further subjected to molecular dynamics simulation studies. The selected ligands could fasten the development of novel treatments for the vast list of movement and central nervous system disorders.Communicated by Ramaswamy H. Sarma.

23 Feb 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Improvement of the Metabolic Stability of GPR88 Agonist RTI-13951-33: Design, Synthesis, and Biological Evaluation

Q1 · MEDICINE

Article

Author: Rahman, Md Toufiqur ; Decker, Ann M. ; Maitra, Rangan ; Perrey, David A. ; Chaminda Lakmal, Hetti Handi ; Kieffer, Brigitte L. ; Darcq, Emmanuel ; Jin, Chunyang ; Ben Hamida, Sami

GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC₅₀ = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists.

01 Jan 2023·Bioorganic & Medicinal Chemistry Letters

Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor

Article

Author: Kormos, Chad M ; Darcq, Emmanuel ; Rahman, Md Toufiqur ; Jin, Chunyang ; Kieffer, Brigitte L ; Decker, Ann M ; Hesk, David

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [³H]RTI-33, derived from a synthetic agonist RTI-13951-33. [³H]RTI-33 has a specific activity of 83.4 Ci/mmol and showed one-site, saturable binding (K_D of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells. A competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.

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Indication	Highest Phase	Country/Location	Organization	Date
Alcoholism	Preclinical	United States	Research Triangle Institute	09 Aug 2018

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