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Papers of the Week

Papers: 30 Nov 2019 - 6 Dec 2019

Animal Studies, Pharmacology/Drug Development

2020 Mar 12

J Med Chem



A novel agonist of the type 1 lysophosphatidic acid receptor (LPA1), UCM-05194, shows efficacy in neuropathic pain amelioration.


Gonzalez Gil I, Zian D, Vázquez-Villa H, Hernandez-Torres G, Martinez FR, Khiar-Fernandez N, Rivera R, Kihara Y, Devesa I, Mathivanan S, Rosell Del Valle C, Zambrana-Infantes E, Puigdomenech M, Cincilla G, Sanchez-Martinez M, de Fonseca F R, Ferrer-Montiel A, Chun J, Lopez-Vales R, López-Rodríguez ML, et al.
J Med Chem. 2020 Mar 12; 63(5):2372-2390.
PMID: 31790581.


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 slightly effective, so there is a need of developing 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 (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax=118%, EC50=0.24 µM, KD=19.6 nM; inactive at autotaxin and LPA2-6 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 in vivo model of NP.