A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration

  • J Med Chem. 2020 Mar 12;63(5):2372-2390. doi: 10.1021/acs.jmedchem.9b01287.
Inés González-Gil  1 ,  Debora Zian  1 ,  Henar Vázquez-Villa  1 ,  Gloria Hernández-Torres  1 ,  R Fernando Martínez  1 ,  Nora Khiar-Fernández  1 ,  Richard Rivera  2 ,  Yasuyuki Kihara  2 ,  Isabel Devesa  3 ,  Sakthikumar Mathivanan  3 ,  Cristina Rosell Del Valle  4 ,  Emma Zambrana-Infantes  4 ,  María Puigdomenech  5 ,  Giovanni Cincilla  6 ,  Melchor Sanchez-Martinez  6 ,  Fernando Rodríguez de Fonseca  4  7 ,  Antonio V Ferrer-Montiel  3 ,  Jerold Chun  2 ,  Rubén López-Vales  5 ,  María L López-Rodríguez  1 ,  Silvia Ortega-Gutiérrez  1
Affiliations
  • 1. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
  • 2. Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
  • 3. IDiBE, Universidad Miguel Hernández de Elche, E-03202 Alicante, Spain.
  • 4. Instituto de Investigación Biomédica de Málaga, UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, E-29010 Málaga, Spain.
  • 5. Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, E-08193 Barcelona, Spain.
  • 6. Molomics, Barcelona Science Park, Baldiri i Reixac 4-8, E-08028 Barcelona, Spain.
  • 7. Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, Pozuelo de Alarcón, E-28223 Madrid, Spain.
PMID: 31790581 DOI: 10.1021/acs.jmedchem.9b01287
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.

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