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An anchor-tether 'hindered' HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model.
Tibbs, Gareth R; Uprety, Rajendra; Warren, J David; Beyer, Nicole P; Joyce, Rebecca L; Ferrer, Matthew A; Mellado, Wilfredo; Wong, Victor S C; Goldberg, David C; Cohen, Melanie W; Costa, Christopher J; Li, Zhucui; Zhang, Guoan; Dephoure, Noah E; Barman, Dipti N; Sun, Delin; Ingólfsson, Helgi I; Sauve, Anthony A; Willis, Dianna E; Goldstein, Peter A.
Afiliación
  • Tibbs GR; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
  • Uprety R; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • Warren JD; Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
  • Beyer NP; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
  • Joyce RL; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
  • Ferrer MA; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
  • Mellado W; Burke Neurological Institute, White Plains, NY, USA.
  • Wong VSC; Burke Neurological Institute, White Plains, NY, USA.
  • Goldberg DC; Burke Neurological Institute, White Plains, NY, USA.
  • Cohen MW; Burke Neurological Institute, White Plains, NY, USA.
  • Costa CJ; Burke Neurological Institute, White Plains, NY, USA.
  • Li Z; Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
  • Zhang G; Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
  • Dephoure NE; Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • Barman DN; Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA.
  • Sun D; Lawrence Livermore National Laboratory, Livermore, CA, USA.
  • Ingólfsson HI; Lawrence Livermore National Laboratory, Livermore, CA, USA.
  • Sauve AA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • Willis DE; Burke Neurological Institute, White Plains, NY, USA; Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, New York, NY, USA. Electronic address: diw2004@med.cornell.edu.
  • Goldstein PA; Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA; Feil Family Brain & Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA. Electronic address: pag2014@med.cornell.edu.
Br J Anaesth ; 131(4): 745-763, 2023 10.
Article en En | MEDLINE | ID: mdl-37567808
BACKGROUND: Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. METHODS: In silico molecular dynamics simulation, in vitro electrophysiology, and in vivo rat spared nerve injury methods were used to test whether 'hindered' variants of 26DTB-P (wherein a hydrophilic 'anchor' is attached in the para-position of 26DTB-P via an acyl chain 'tether') had the desired properties. RESULTS: Molecular dynamics simulation showed that membrane penetration of hindered 26DTB-Ps is controlled by a tethered diol anchor without elimination of head group rotational freedom. In vitro and in vivo analysis showed that BP4L-18:1:1, a variant wherein a diol anchor is attached to 26DTB-P via an 18-carbon tether, is an HCN1 inverse agonist and an orally available antihyperalgesic. With a CNS multiparameter optimisation score of 2.25, a >100-fold lower drug load in the brain vs blood, and an absence of adverse cardiovascular or CNS effects, BP4L-18:1:1 was shown to be poorly CNS penetrant and cardiac sparing. CONCLUSIONS: These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agonismo Inverso de Drogas / Neuralgia Tipo de estudio: Prognostic_studies Aspecto: Patient_preference Límite: Animals Idioma: En Revista: Br J Anaesth Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agonismo Inverso de Drogas / Neuralgia Tipo de estudio: Prognostic_studies Aspecto: Patient_preference Límite: Animals Idioma: En Revista: Br J Anaesth Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido