RT Journal Article
T1 A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration.
A1 Gonzalez-Gil, Ines
A1 Zian, Debora
A1 Vazquez-Villa, Henar
A1 Hernandez-Torres, Gloria
A1 Martinez, R Fernando
A1 Khiar-Fernandez, Nora
A1 Rivera, Richard
A1 Kihara, Yasuyuki
A1 Devesa, Isabel
A1 Mathivanan, Sakthikumar
A1 Del Valle, Cristina Rosell
A1 Zambrana-Infantes, Emma
A1 Puigdomenech, Maria
A1 Cincilla, Giovanni
A1 Sanchez-Martinez, Melchor
A1 Rodriguez de Fonseca, Fernando
A1 Ferrer-Montiel, Antonio V
A1 Chun, Jerold
A1 Lopez-Vales, Ruben
A1 Lopez-Rodriguez, Maria L
A1 Ortega-Gutierrez, Silvia
K1 Analgesics
K1 Animals
K1 Cell line
K1 Cell movement
K1 Cells, cultured
AB 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.
PB American Chemical Society
YR 2019
FD 2019-12-16
LK http://hdl.handle.net/10668/14777
UL http://hdl.handle.net/10668/14777
LA en
NO González-Gil I, Zian D, Vázquez-Villa H, Hernández-Torres G, Martínez RF, Khiar-Fernández N, et al. 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
NO This work has been awarded with the Almirall Prize for Young Researchers from the Sociedad Española de Química Terapéutica (SEQT) to I.G.-G. This work has been supported by the Spanish Ministerio de Economía y Competitividad (MINECO, Grants SAF2016-78792-R to M.L.L.-R. and S.O.-G., SAF2015-66275-C2-1 and RTI2018-097189-B-C21 to A.V.F.-M., and SAF2016-79774-R to R.L.-V.), Wings for Life International Foundation, and Red de Terapia Celular (TERCEL) to R.L.-V, Instituto de Salud Carlos III MINECO and Regional Development Funds-European Union (ERdf-EU) (Grant PI16/01698 to F.R.F.) and National Institutes of Health (NS084398 to J.C.). The authors thank MINECO for predoctoral F.P.U. grants to I.G.-G and D.Z. RH7777 hepatoma cells stably expressing the LPA1 receptor and their corresponding non-transfected controls were kindly provided by Prof. Gabor Tigyi (University of Tennessee Health Science Center, Memphis, Tennessee). Retrovirus expression vector (LZRS-EGFP) and Phoenix retrovirus producer cell lines were provided by Prof. Garry P. Nolan (Stanford University, Stanford, California).
DS RISalud
RD Apr 12, 2025