A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
Year: 2019
Type: article
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 (LPA 1 ) 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 LPA 1 agonists among which derivative ( S )- 17 (UCM-05194) stands out as the most potent and selective LPA 1 receptor agonist described so far ( E max = 118%, EC 50 = 0.24 μM, K D = 19.6 nM; inactive at autotaxin and LPA 2–6 receptors). This compound induces characteristic LPA 1 -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.
Source: Journal of Medicinal Chemistry
Authors: 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
Institutions: Universidad Complutense de Madrid, Sanford Burnham Prebys Medical Discovery Institute, Universitat de Miguel Hernández d'Elx, Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Universitat Autònoma de Barcelona, Biomedical Research Networking Center on Neurodegenerative Diseases, Parc Científic de Barcelona
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1075404386, G1777144918, G213944693, G2708544407, G4616156949, Lípidos transmisores derivados del ácido oleico: Estudio traslacional de su papel en los trastornos por uso de alcohol, G5215989529, G6442945850, G6507516830, Prenatal blood-borne lipids in post-hemorrhagic hydrocephalus, G7309386017
OpenAlex ID: W2994234749