A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
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2019
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American Chemical Society
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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
Abstract
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.