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Lysophosphatidic acid (LPA) is the natural ligand for two phylogenetically distinct families of receptors (LPA 1-3, LPA 4-6 ) whose pathways control a variety of physiologic and pathophysiological responses. Identifying the benefit of balanced activation/repression of LPA receptors has always been a challenge because of the high lability of LPA and the limited availability of selective and/or stable agonists. In this study, we document the discovery of small benzofuran ethanolamine derivatives (called CpX and CpY) behaving as LPA 1-3 agonists. Initially found as rabbit urethra contracting agents, their elusive receptors were identified from [ 35 S]GTP γ S-binding and β -arrestin2 recruitment investigations and then confirmed by [ 3 H]CpX binding studies (urethra, hLPA 1-2 membranes). Both compounds induced a calcium response in hLPA 1-3 cells within a range of 0.4-1.5-log lower potency as compared with LPA. The contractions of rabbit urethra strips induced by these compounds perfectly matched binding affinities with values reaching the two-digit nanomolar level. The antagonist, KI16425, dose-dependently antagonized CpX-induced contractions in agreement with its affinity profile (LPA 1 ≥LPA 3 &gt;&gt;LPA 2 ). The most potent agonist, CpY, doubled intraurethral pressure in anesthetized female rats at 3 µg/kg i.v. Alternatively, CpX was shown to inhibit human preadipocyte differentiation, a process totally reversed by KI16425. Together with original molecular docking data, these findings clearly established these molecules as potent agonists of LPA 1-3 and consolidated the pivotal role of LPA 1 in urethra/prostate contraction as well as in fat cell development. The discovery of these unique and less labile LPA 1-3 agonists would offer new avenues to investigate the roles of LPA receptors. SIGNIFICANCE STATEMENT: We report the identification of benzofuran ethanolamine derivatives behaving as potent selective nonlipid LPA 1-3 agonists and shown to alter urethra muscle contraction or preadipocyte differentiation. Unique at this level of potency, selectivity, and especially stability, compared with lysophosphatidic acid, they represent more appropriate tools for investigating the physiological roles of lysophosphatidic acid receptors and starting point for optimization of drug candidates for therapeutic applications.

Lysophosphatidic Acid Receptor Agonism: Discovery of Potent Nonlipid Benzofuran Ethanolamine Structures