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

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

doi:10.1016/j.bmcl.2022.129120

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

Bioorg Med Chem Lett. 2023 Jan 15:80:129120. doi: 10.1016/j.bmcl.2022.129120. Epub 2022 Dec 29.

Authors

Ann M Decker¹, Md Toufiqur Rahman², Chad M Kormos³, David Hesk⁴, Emmanuel Darcq⁵, Brigitte L Kieffer⁶, Chunyang Jin⁷

Affiliations

¹ Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA. Electronic address: adecker@rti.org.
² Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA. Electronic address: mrahman@rti.org.
³ Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA. Electronic address: ckormos@rti.org.
⁴ Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA. Electronic address: dhesk@rti.org.
⁵ INSERM U1114, University of Strasbourg, Strasbourg 67085, France. Electronic address: edarcq@unistra.fr.
⁶ INSERM U1114, University of Strasbourg, Strasbourg 67085, France. Electronic address: brigitte.kieffer@unistra.fr.
⁷ Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, USA. Electronic address: cjin@rti.org.

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, [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.

Keywords: GPR88; Radioligand binding; [(3)H]RTI-33.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Carrier Proteins*
Cricetinae
Cricetulus
Radioligand Assay
Receptors, G-Protein-Coupled* / agonists

Substances

Receptors, G-Protein-Coupled
Carrier Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding