Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain
Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/11/3617 |
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| author | Lisa L. Wilson Amy R. Alleyne Shainnel O. Eans Thomas J. Cirino Heather M. Stacy Marco Mottinelli Sebastiano Intagliata Christopher R. McCurdy Jay P. McLaughlin |
| author_facet | Lisa L. Wilson Amy R. Alleyne Shainnel O. Eans Thomas J. Cirino Heather M. Stacy Marco Mottinelli Sebastiano Intagliata Christopher R. McCurdy Jay P. McLaughlin |
| author_sort | Lisa L. Wilson |
| collection | DOAJ |
| description | Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10–45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED<sub>50</sub> (and 95% C.I.) = 14.7 (10.6–20) mg/kg, i.p.) and the formalin assay (ED<sub>50</sub> (and 95% C.I.) = 0.86 (0.44–1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain. |
| first_indexed | 2024-03-10T01:02:48Z |
| format | Article |
| id | doaj.art-b52e94dd1a3a49688fc681766bfc0bd2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T01:02:48Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b52e94dd1a3a49688fc681766bfc0bd22023-11-23T14:31:41ZengMDPI AGMolecules1420-30492022-06-012711361710.3390/molecules27113617Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic PainLisa L. Wilson0Amy R. Alleyne1Shainnel O. Eans2Thomas J. Cirino3Heather M. Stacy4Marco Mottinelli5Sebastiano Intagliata6Christopher R. McCurdy7Jay P. McLaughlin8Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USADepartment of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USASigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10–45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED<sub>50</sub> (and 95% C.I.) = 14.7 (10.6–20) mg/kg, i.p.) and the formalin assay (ED<sub>50</sub> (and 95% C.I.) = 0.86 (0.44–1.81) mg/kg, i.p.) but was without effect in the 55 °C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain.https://www.mdpi.com/1420-3049/27/11/3617sigmasigma-2 receptorsigma-2 ligandallodyniaanalgesianeuropathic pain |
| spellingShingle | Lisa L. Wilson Amy R. Alleyne Shainnel O. Eans Thomas J. Cirino Heather M. Stacy Marco Mottinelli Sebastiano Intagliata Christopher R. McCurdy Jay P. McLaughlin Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain Molecules sigma sigma-2 receptor sigma-2 ligand allodynia analgesia neuropathic pain |
| title | Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain |
| title_full | Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain |
| title_fullStr | Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain |
| title_full_unstemmed | Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain |
| title_short | Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain |
| title_sort | characterization of cm 398 a novel selective sigma 2 receptor ligand as a potential therapeutic for neuropathic pain |
| topic | sigma sigma-2 receptor sigma-2 ligand allodynia analgesia neuropathic pain |
| url | https://www.mdpi.com/1420-3049/27/11/3617 |
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