Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice

Abstract

Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (σ1R) is known to be a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Conversely, relatively little is known about σ2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of σ1R and σ2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model. In agreement with previous reports, we find that σ1R ligands given intrathecally (IT) produce relief of SNI-induced mechanical hypersensitivity. We also find that the putative σ2R/Tmem97 agonists DKR-1005, DKR-1051, and UKH-1114 (Ki ~ 46 nM) lead to relief of SNI-induced mechanical hypersensitivity, peaking at 48 h after dosing when given IT. This effect is blocked by the putative σ2R/Tmem97 antagonist SAS-0132. Systemic administration of UKH-1114 (10 mg/kg) relieves SNI-induced mechanical hypersensitivity for 48 h with a peak magnitude of effect equivalent to 100 mg/kg gabapentin and without producing any motor impairment. Finally, we find that the TMEM97 gene is expressed in mouse and human dorsal root ganglion (DRG) including populations of neurons that are involved in pain; however, the gene is also likely expressed in non-neuronal cells that may contribute to the observed behavioral effects. Our results show robust antineuropathic pain effects of σ1R and σ2R/Tmem97 ligands, demonstrate that σ2R/Tmem97 is a novel neuropathic pain target, and identify UKH-1114 as a lead molecule for further development.

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

“…8,19,22 e Differs from previously published values due to averaging of additional of K i measurements. 8,22 …”

“…11,12 σ 2R/TMEM97 has long been associated with cancer, 13,14 and it is increasingly being implicated in cellular processes relevant to a variety of CNS disorders, 10,15 including Alzheimer's disease (AD), 8,16–18 schizophrenia, 10 anxiety, pain, 19 and Niemann-Pick disease. 12 …”

BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation

“…(2) S2R was implicated (via pharmacology) in neurological diseases 19 (e.g. Alzheimer's) 20 , psychiatric disorders 6,21 , and cancers 22 .…”

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors

“…1) that exhibit high affinity and selectivity for σ2R/Tmem97 [19][20][21][22]. Several of these σ2R/Tmem97 modulators show therapeutic effects in animal models of central nervous system (CNS) disorders [23,24]. For example, the piperazine derivative SAS-0132 improves cognitive performance in a transgenic animal model of Alzheimer's disease (AD) ( Fig.…”

“…For example, the piperazine derivative SAS-0132 improves cognitive performance in a transgenic animal model of Alzheimer's disease (AD) ( Fig. 1a) [24], whereas the biaryls UKH-1114 and DKR-1051 reduce mechanical hypersensitivity in an animal model of neuropathic pain [23]. In a different study, DKR-1051 induced a rapid Ca 2+ transient when applied to SKH-neuroblastoma cells that was blocked by SAS-0132 [24].…”