• Gareth R Tibbs, Rajendra Uprety, J David Warren, Nicole P Beyer, Rebecca L Joyce, Matthew A Ferrer, Wilfredo Mellado, Victor S C Wong, David C Goldberg, Melanie W Cohen, Christopher J Costa, Zhucui Li, Guoan Zhang, Noah E Dephoure, Dipti N Barman, Delin Sun, Helgi I Ingólfsson, Anthony A Sauve, Dianna E Willis, and Peter A Goldstein.
• Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
• Br J Anaesth. 2023 Oct 1; 131 (4): 745763745-763.

BackgroundNeuropathic 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.MethodsIn 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.ResultsMolecular 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.ConclusionsThese findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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