title: Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies.
abstract: GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a Gαi-coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4'-substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop.
authors: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors: Chunyang
authors: C
authors: Jin
authors: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors: Ann M
authors: AM
authors: Decker
authors: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors: Danni L
authors: DL
authors: Harris
authors: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors: Bruce E
authors: BE
authors: Blough
mesh_terms: D000595:Amino Acid Sequence; D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003412:Cricetulus; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D010133:p-Chloroamphetamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D002839:Chromans; C418740:GPR88 protein, human; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; C029201:2-(4-chlorophenyl)cyclopropylamine; D010133:p-Chloroamphetamine; C023650:aniline
keywords: 2-PCCA; Orphan GPR88; SAR; molecular modeling