title: Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists.
abstract: The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαiproteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance.
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, United States. Electronic address: cjin@rti.org.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Jin
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC 27709, United States.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Langston
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005026:Ethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D005026:Ethylene Glycols; C418740:GPR88 protein, human; D010636:Phenols; D043562:Receptors, G-Protein-Coupled; C034604:4-hydroxyphenethylene glycol; C023010:4-hydroxyphenylglycine; D005998:Glycine
keywords: 2-AMPP; 2-PCCA; Agonist; GPR88; SAR