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 Gα_i-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., <b>5j</b>, <b>5o</b>) 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