A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA₁), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration

Abstract

Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and weakly effective, so there is a need to develop more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA₁) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA₁ agonists among which derivative (<i>S</i>)-<b>17</b> (UCM-05194) stands out as the most potent and selective LPA₁ receptor agonist described so far (<i>E</i>_max = 118%, EC₅₀ = 0.24 μM, <i>K</i>_D = 19.6 nM; inactive at autotaxin and LPA_2-6 receptors). This compound induces characteristic LPA₁-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an <i>in vivo</i> model of NP.