A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain
The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neur...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-05-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224003561 |
| _version_ | 1797244998669828096 |
|---|---|
| author | Franz Kricek Christine Ruf Premji Meghani Ivana A. Souza Maria A. Gandini Gerald W. Zamponi George Skouteris |
| author_facet | Franz Kricek Christine Ruf Premji Meghani Ivana A. Souza Maria A. Gandini Gerald W. Zamponi George Skouteris |
| author_sort | Franz Kricek |
| collection | DOAJ |
| description | The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of chronic neuropathic pain. Gabapentinoids, such as gabapentin and pregabalin, engage with Cavα2δ-1 via binding an arginine residue (R241) within an RRR motif located at the N-terminus of human Cavα2δ-1. A novel, next generation gabapentinoid, engineered not to penetrate the brain, was able to generate a strong analgesic response in Chronic Constriction Injury animal model of chronic neuropathic pain and showed binding specificity for Cavα2δ-1 versus the Cavα2δ-2 subunit. This novel non-brain penetrant gabapentinoid, binds to R241 and a novel binding site on Cavα2δ-1, which is located within the VGCC_α2 domain, identified as a lysine residue within an IKAK amino acid motif (K634). The overall whole cell current amplitudes were diminished by the compound, with these inhibitory effects being diminished in R241A mutant Cavα2δ-1 subunits. The functional effects occurred at lower concentrations than those needed for inhibition by gabapentin or pregabalin, which apparently bound the Cavα2δ-1 subunit only on the R241 and not on the K634 residue. Our work sets the stage for the identification and characterisation of novel compounds with therapeutic properties in neuropathic pain and possibly in other disorders and conditions which require engagement of the Cavα2δ-1 target. |
| first_indexed | 2024-04-24T19:19:55Z |
| format | Article |
| id | doaj.art-a907b72b95b0430185c1465eca18b428 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-24T19:19:55Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-a907b72b95b0430185c1465eca18b4282024-03-26T04:26:32ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-05-01174116472A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic painFranz Kricek0Christine Ruf1Premji Meghani2Ivana A. Souza3Maria A. Gandini4Gerald W. Zamponi5George Skouteris6Department of Experimental Neurosciences, Novassay SA, Biopôle, Epalinges 1066, Switzerland; NBS-C BioScience GmbH, Vienna 1230, AustriaNBS-C BioScience GmbH, Vienna 1230, AustriaDepartment of Experimental Neurosciences, Novassay SA, Biopôle, Epalinges 1066, SwitzerlandDepartment of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, T2N 4N1, CanadaDepartment of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, T2N 4N1, CanadaDepartment of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, University of Calgary, T2N 4N1, CanadaDepartment of Experimental Neurosciences, Novassay SA, Biopôle, Epalinges 1066, Switzerland; 3A Laboratories, Stevenage Bioscience Catalyst (SBC), Stevenage SG1 2FX, United Kingdom; Corresponding author at: Department of Experimental Neurosciences, Novassay SA, Biopôle, Epalinges 1066, Switzerland.The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of chronic neuropathic pain. Gabapentinoids, such as gabapentin and pregabalin, engage with Cavα2δ-1 via binding an arginine residue (R241) within an RRR motif located at the N-terminus of human Cavα2δ-1. A novel, next generation gabapentinoid, engineered not to penetrate the brain, was able to generate a strong analgesic response in Chronic Constriction Injury animal model of chronic neuropathic pain and showed binding specificity for Cavα2δ-1 versus the Cavα2δ-2 subunit. This novel non-brain penetrant gabapentinoid, binds to R241 and a novel binding site on Cavα2δ-1, which is located within the VGCC_α2 domain, identified as a lysine residue within an IKAK amino acid motif (K634). The overall whole cell current amplitudes were diminished by the compound, with these inhibitory effects being diminished in R241A mutant Cavα2δ-1 subunits. The functional effects occurred at lower concentrations than those needed for inhibition by gabapentin or pregabalin, which apparently bound the Cavα2δ-1 subunit only on the R241 and not on the K634 residue. Our work sets the stage for the identification and characterisation of novel compounds with therapeutic properties in neuropathic pain and possibly in other disorders and conditions which require engagement of the Cavα2δ-1 target.http://www.sciencedirect.com/science/article/pii/S0753332224003561Chronic PainVGCCCACNA2D1Gabapentinoids |
| spellingShingle | Franz Kricek Christine Ruf Premji Meghani Ivana A. Souza Maria A. Gandini Gerald W. Zamponi George Skouteris A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain Biomedicine & Pharmacotherapy Chronic Pain VGCC CACNA2D1 Gabapentinoids |
| title | A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain |
| title_full | A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain |
| title_fullStr | A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain |
| title_full_unstemmed | A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain |
| title_short | A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain |
| title_sort | next generation peripherally restricted cavα2δ 1 ligand with inhibitory action on cav2 2 channels and utility in neuropathic pain |
| topic | Chronic Pain VGCC CACNA2D1 Gabapentinoids |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224003561 |
| work_keys_str_mv | AT franzkricek anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT christineruf anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT premjimeghani anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT ivanaasouza anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT mariaagandini anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT geraldwzamponi anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT georgeskouteris anextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT franzkricek nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT christineruf nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT premjimeghani nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT ivanaasouza nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT mariaagandini nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT geraldwzamponi nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain AT georgeskouteris nextgenerationperipherallyrestrictedcava2d1ligandwithinhibitoryactiononcav22channelsandutilityinneuropathicpain |