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*Silvia Ortega-Gutiérrez

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

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.

Original languageAmerican English
Pages (from-to)2372-2390
Number of pages19
JournalJournal of Medicinal Chemistry
Volume63
Issue number5
DOIs
Publication statusPublished - 12 Mar 2020

Fingerprint

Dive into the research topics of 'A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA<sub>1</sub>), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration'. Together they form a unique fingerprint.

Cite this