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Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models.
Belgi, Alessia; Burnley, James V; MacRaild, Christopher A; Chhabra, Sandeep; Elnahriry, Khaled A; Robinson, Samuel D; Gooding, Simon G; Tae, Han-Shen; Bartels, Peter; Sadeghi, Mahsa; Zhao, Fei-Yue; Wei, Haifeng; Spanswick, David; Adams, David J; Norton, Raymond S; Robinson, Andrea J.
Affiliation
  • Belgi A; School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
  • Burnley JV; School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
  • MacRaild CA; Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Chhabra S; Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Elnahriry KA; Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Robinson SD; Medicinal Chemistry, Monash Institute of Pharmaceutical Science, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
  • Gooding SG; School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
  • Tae HS; Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • Bartels P; Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • Sadeghi M; Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • Zhao FY; NeuroSolutions Ltd., Coventry CV4 7AL, U.K.
  • Wei H; NeuroSolutions Ltd., Coventry CV4 7AL, U.K.
  • Spanswick D; NeuroSolutions Ltd., Coventry CV4 7AL, U.K.
  • Adams DJ; Biomedicine Discovery Institute and the Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
  • Norton RS; Warwick Medical School, University of Warwick, Coventry CV4 7AL, U.K.
  • Robinson AJ; Illawarra Health & Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia.
J Med Chem ; 64(6): 3222-3233, 2021 03 25.
Article in En | MEDLINE | ID: mdl-33724033
ABSTRACT
Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Conotoxins / Alkynes / Hyperalgesia / Analgesics / Neuralgia Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Conotoxins / Alkynes / Hyperalgesia / Analgesics / Neuralgia Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article Affiliation country: Australia