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

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.

Platinum-Based Drugs Cause Mitochondrial Dysfunction in Cultured Dorsal Root Ganglion Neurons

“…Therefore, these neurons express a specialized setup of receptors and channels that can be activated by mechanical, thermal, or chemical stimuli and contribute to typical symptoms of CIPN as hyperalgesia, allodynia, or numbness ([ 13 , 14 , 15 ]. Several of these receptors or channels such as voltage-gated calcium channels or type 1 lysophosphatidic acid (LPA 1 ) receptors are discussed as playing a critical role in the induction of polyneuropathies or neuropathic pain in different models ([ 16 , 17 , 18 , 19 , 20 ]. Several cation channels facilitate nociception, e.g., the transient receptor potential channels (TRP), a family of cation channels that are crucial transducers of nociceptive stimuli contributing to sensory input.…”

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

“…Phase 2 clinical trials conducted with BMS-986020 ( 48 ), a potent LPA1 receptor antagonist, demonstrated that LPA1 receptor antagonists are effective in treating idiopathic pulmonary fibrosis; however, the study was terminated due to hepatotoxicity . Compounds such as 49 and UCM-05194 ( 50 ) which are LPA1 agonists have also been identified . Interestingly, 50 showed remarkable efficacy in reducing neuropathic pain in the mouse spared nerve injury (SNI) model of neuropathic pain .…”

“…Compounds such as 49 and UCM-05194 ( 50 ) which are LPA1 agonists have also been identified . Interestingly, 50 showed remarkable efficacy in reducing neuropathic pain in the mouse spared nerve injury (SNI) model of neuropathic pain . Thus, both LPA1 antagonists which block the LPA1 receptor and LPA1 agonists which cause desensitization of the receptor can be pursued in the development of novel treatments for neuropathic pain.…”

Dual Role of Lysophosphatidic Acid Receptor 2 (LPA2) in Amyotrophic Lateral Sclerosis

“…LPA is a lysophospholipid that is a potent lipid-signaling molecule with many different actions in the CNS including neural development (Hecht et al, 1996 ), axonal retraction (Bräuer et al, 2003 ; Broggini et al, 2010 ), neuronal death (Kingsbury et al, 2003 ; Steiner et al, 2006 ; Ramesh et al, 2018 ; Zhang et al, 2020 ), and inflammation (Kwon et al, 2018 ; Plastira et al, 2020 ). Moreover, LPA signaling has been related to various neurological disorders including psychiatric diseases (Mirendil et al, 2015 ; Yamada et al, 2015 ; Schneider et al, 2018 ; Tabbai et al, 2019 ), Alzheimer’s disease (Hwang et al, 2012 ; Shi et al, 2013 ; Ramesh et al, 2018 ) spinal cord injury (Goldshmit et al, 2012 ; Santos-Nogueira et al, 2015 ; López-Serrano et al, 2019 ), and the appearance of neuropathic pain responses (Lin et al, 2012 ; Ueda et al, 2013 , 2018 ; González-Gil et al, 2020 ).…”