title: Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor.
abstract: GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands. In this paper, we report the synthesis of a GPR88 agonist 2-PCCA and its pure diastereomers, which were functionally characterized in both transiently and stably expressing GPR88 HEK293 cells. 2-PCCA inhibited isoproterenol-stimulated cAMP accumulation in a concentration-dependent manner in cells expressing GPR88 but not in the control cells, suggesting that the observed cAMP inhibition is mediated through GPR88 and that GPR88 is coupled to Gαi. 2-PCCA did not induce calcium mobilization in GPR88 cells, indicating no Gαq-mediated response. A structure-activity relationship (SAR) study of 2-PCCA was also conducted to explore the key structural features for GPR88 agonist activity.
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jin
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Brian P
authors.initials: BP
authors.lastname: Gilmour
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Yang
authors.initials: Y
authors.lastname: Hu
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Gill
authors.forename: X Peter
authors.initials: XP
authors.lastname: Zhang
mesh_terms: D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D014162:Transfection; D010133:p-Chloroamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002839:Chromans; C418740:GPR88 protein, human; D043562:Receptors, G-Protein-Coupled; C029201:2-(4-chlorophenyl)cyclopropylamine; D010133:p-Chloroamphetamine; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol; D002118:Calcium