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00925njm 22002777a 4500 dc González Gil, Inés author Zian, Debora author Vázquez Villa, María Del Henar author Hernández Torres, Gloria author Martínez, R. Fernando author Khiar Fernández, Nora author Rivera, Richard author Kihara, Yasuyuki author Devesa, Isabel author Mathivanan, Sakthikumar author Rosell del Valle, Cristina author Zambrana Infantes, Emma author Puigdomenech, María author Cincilla, Giovanni author Sánchez Martínez, Melchor author Rodríguez De Fonseca, Fernando Antonio author Ferrer Montiel, Antonio V. author Chun, Jerold author López Vales, Ruben author López Rodríguez, María Luz author Ortega Gutiérrez, Silvia author 2019-12-02 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 (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. A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration Inés González-Gil, Debora Zian, Henar Vázquez-Villa, Gloria Hernández-Torres, R. Fernando Martínez, Nora Khiar-Fernández, Richard Rivera, Yasuyuki Kihara, Isabel Devesa, Sakthikumar Mathivanan, Cristina Rosell del Valle, Emma Zambrana-Infantes, María Puigdomenech, Giovanni Cincilla, Melchor Sanchez-Martinez, Fernando Rodríguez de Fonseca, Antonio V. Ferrer-Montiel, Jerold Chun, Rubén López-Vales, María L. López-Rodríguez, and Silvia Ortega-Gutiérrez Journal of Medicinal Chemistry 2020 63 (5), 2372-2390 DOI: 10.1021/acs.jmedchem.9b01287 10.1021/acs.jmedchem.9b01287 https://hdl.handle.net/20.500.14352/103163 A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration