An anchor-tether ‘hindered’ HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model
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...
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| Published in | British journal of anaesthesia : BJA Vol. 131; no. 4; pp. 745 - 763 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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England
Elsevier Ltd
01.10.2023
Elsevier |
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| Abstract | 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.
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.
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.
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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| AbstractList | 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.
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.
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.
These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets. 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.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.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.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.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.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.These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.CONCLUSIONSThese findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets. |
| Author | Joyce, Rebecca L. Sun, Delin Barman, Dipti N. Sauve, Anthony A. Warren, J. David Costa, Christopher J. Mellado, Wilfredo Ferrer, Matthew A. Dephoure, Noah E. Zhang, Guoan Cohen, Melanie W. Beyer, Nicole P. Wong, Victor S.C. Willis, Dianna E. Ingólfsson, Helgi I. Goldberg, David C. Tibbs, Gareth R. Uprety, Rajendra Goldstein, Peter A. Li, Zhucui |
| Author_xml | – sequence: 1 givenname: Gareth R. orcidid: 0000-0003-1494-5833 surname: Tibbs fullname: Tibbs, Gareth R. organization: Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA – sequence: 2 givenname: Rajendra orcidid: 0000-0003-1190-5318 surname: Uprety fullname: Uprety, Rajendra organization: Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 3 givenname: J. David orcidid: 0000-0002-2833-2248 surname: Warren fullname: Warren, J. David organization: Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA – sequence: 4 givenname: Nicole P. orcidid: 0009-0005-4968-8680 surname: Beyer fullname: Beyer, Nicole P. organization: Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA – sequence: 5 givenname: Rebecca L. orcidid: 0009-0004-8265-9737 surname: Joyce fullname: Joyce, Rebecca L. organization: Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA – sequence: 6 givenname: Matthew A. orcidid: 0009-0008-4488-8511 surname: Ferrer fullname: Ferrer, Matthew A. organization: Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA – sequence: 7 givenname: Wilfredo orcidid: 0000-0003-4665-5961 surname: Mellado fullname: Mellado, Wilfredo organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 8 givenname: Victor S.C. surname: Wong fullname: Wong, Victor S.C. organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 9 givenname: David C. surname: Goldberg fullname: Goldberg, David C. organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 10 givenname: Melanie W. surname: Cohen fullname: Cohen, Melanie W. organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 11 givenname: Christopher J. orcidid: 0000-0002-2648-0757 surname: Costa fullname: Costa, Christopher J. organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 12 givenname: Zhucui surname: Li fullname: Li, Zhucui organization: Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA – sequence: 13 givenname: Guoan surname: Zhang fullname: Zhang, Guoan organization: Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA – sequence: 14 givenname: Noah E. orcidid: 0000-0001-5802-2657 surname: Dephoure fullname: Dephoure, Noah E. organization: Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA – sequence: 15 givenname: Dipti N. surname: Barman fullname: Barman, Dipti N. organization: Department of Biochemistry, Weill Cornell Medicine, New York, NY, USA – sequence: 16 givenname: Delin surname: Sun fullname: Sun, Delin organization: Lawrence Livermore National Laboratory, Livermore, CA, USA – sequence: 17 givenname: Helgi I. orcidid: 0000-0002-7613-9143 surname: Ingólfsson fullname: Ingólfsson, Helgi I. organization: Lawrence Livermore National Laboratory, Livermore, CA, USA – sequence: 18 givenname: Anthony A. surname: Sauve fullname: Sauve, Anthony A. organization: Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA – sequence: 19 givenname: Dianna E. surname: Willis fullname: Willis, Dianna E. email: diw2004@med.cornell.edu organization: Burke Neurological Institute, White Plains, NY, USA – sequence: 20 givenname: Peter A. orcidid: 0000-0002-5973-9104 surname: Goldstein fullname: Goldstein, Peter A. email: pag2014@med.cornell.edu organization: Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA |
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| Keywords | neuropathic pain rat ion channel nerve injury antihyperalgesia HCN1 |
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| SubjectTerms | Animals antihyperalgesia Drug Inverse Agonism Electrophysiological Phenomena HCN1 Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - therapeutic use ion channel nerve injury Neuralgia - drug therapy neuropathic pain Pain Quality of Life rat Rats |
| Title | An anchor-tether ‘hindered’ HCN1 inhibitor is antihyperalgesic in a rat spared nerve injury neuropathic pain model |
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