A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA(1)), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
| Autor: | Giovanni Cincilla, Cristina Rosell del Valle, Rubèn López-Vales, Silvia Ortega-Gutiérrez, Maria Puigdomenech, Fernando Rodríguez de Fonseca, Melchor Sanchez-Martinez, Jerold Chun, Gloria Hernández-Torres, Antonio Ferrer-Montiel, Debora Zian, María L. López-Rodríguez, Isabel Devesa, Sakthikumar Mathivanan, Richard Rivera, Henar Vázquez-Villa, R Fernando Martínez, Inés González-Gil, Yasuyuki Kihara, Nora Khiar-Fernández, Emma Zambrana-Infantes |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Agonist Sensory Receptor Cells medicine.drug_class media_common.quotation_subject Population Pharmacology Hydrocarbons Aromatic 01 natural sciences Cell Line 03 medical and health sciences chemistry.chemical_compound Cell Movement Drug Discovery Lysophosphatidic acid medicine Animals Humans Rats Wistar Receptors Lysophosphatidic Acid Internalization education Receptor Cells Cultured 030304 developmental biology media_common Analgesics 0303 health sciences education.field_of_study Chronic pain Pain Perception medicine.disease 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry chemistry Neuropathic pain Neuralgia Molecular Medicine Female lipids (amino acids peptides and proteins) Autotaxin |
| Zdroj: | J MED CHEM r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante instname |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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