Synthesis and pharmacological validation of a novel radioligand for the orphan GPR88 receptor. (15th January 2023)

• Record Type: Journal Article
• Authors: Decker, Ann M.; Rahman, Md Toufiqur; Kormos, Chad M.; Hesk, David; Darcq, Emmanuel; Kieffer, Brigitte L.; Jin, Chunyang
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 80(2023)
• Publication Date: 2023-01-15
• Subjects: GPR88 -- [3H]RTI-33 -- Radioligand binding; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129120
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: [ 3 H]RTI-33 is the first radioligand for the GPR88 receptor. [ 3 H]RTI-33 has high affinity for GPR88 in PPLS-HA-hGPR88-CHO membranes. GPR88 functional agonists competitively displace [ 3 H]RTI-33. Abstract: 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, [ 3 H]RTI-33, derived from a synthetic agonist RTI-13951-33. [ 3 H]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.