Alkylphenol inverse agonists of HCN1 gating: H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency.

Amino Acid Sequence Animals Cryoelectron Microscopy Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / chemistry Ion Channel Gating / drug effects Mice Models, Molecular Oocytes / drug effects Phenols / chemistry Potassium Channels / chemistry Protein Conformation Protein Isoforms Structure-Activity Relationship Xenopus laevis
2-Fluoro-13-di-iso-propylbenzene Alkylphenol Anti-hyperalgesia Cyclohexanol HCN channels Inverse agonists Kinetic modeling Neuropathic pain Phenyl-fluorine Phenyl-isocyanate Phenyl-thiol Propofol

Journal

Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032

Informations de publication

Date de publication:
05 2019
Historique:
received: 29 11 2018
accepted: 11 02 2019
pubmed: 16 2 2019
medline: 9 1 2020
entrez: 16 2 2019
Statut: ppublish

Résumé

In models of neuropathic pain, inhibition of HCN1 is anti-hyperalgesic. 2,6-di-iso-propyl phenol (propofol) and its non-anesthetic congener, 2,6-di-tert-butyl phenol, inhibit HCN1 channels by stabilizing closed state(s). Using in vitro electrophysiology and kinetic modeling, we systematically explore the contribution of ligand architecture to alkylphenol-channel coupling. When corrected for changes in hydrophobicity (and propensity for intra-membrane partitioning), the decrease in potency upon 1-position substitution (NCO∼OH >> SH >>> F) mirrors the ligands' H-bond acceptor (NCO > OH > SH >>> F) but not donor profile (OH > SH >>> NCO∼F). H-bond elimination (OH to F) corresponds to a ΔΔG of ∼4.5 kCal mol A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å

Sections du résumé

BACKGROUND AND PURPOSE
In models of neuropathic pain, inhibition of HCN1 is anti-hyperalgesic. 2,6-di-iso-propyl phenol (propofol) and its non-anesthetic congener, 2,6-di-tert-butyl phenol, inhibit HCN1 channels by stabilizing closed state(s).
EXPERIMENTAL APPROACH
Using in vitro electrophysiology and kinetic modeling, we systematically explore the contribution of ligand architecture to alkylphenol-channel coupling.
KEY RESULTS
When corrected for changes in hydrophobicity (and propensity for intra-membrane partitioning), the decrease in potency upon 1-position substitution (NCO∼OH >> SH >>> F) mirrors the ligands' H-bond acceptor (NCO > OH > SH >>> F) but not donor profile (OH > SH >>> NCO∼F). H-bond elimination (OH to F) corresponds to a ΔΔG of ∼4.5 kCal mol
CONCLUSIONS AND IMPLICATIONS
A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å

Identifiants

DOI: 10.1016/j.bcp.2019.02.013 PMID: 30768926 PMC: PMC6599521
pubmed: 30768926
pii: S0006-2952(19)30051-6
doi: 10.1016/j.bcp.2019.02.013
pmc: PMC6599521
mid: NIHMS1525523
pii:
doi:

Substances chimiques

Hcn1 protein, mouse 0
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels 0
Phenols 0
Potassium Channels 0
Protein Isoforms 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

493-508

Subventions

Organisme : NIGMS NIH HHS
ID : P01 GM055876
Pays : United States

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

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Auteurs

Rebecca L Joyce (RL)

Weill Cornell Medicine, New York, NY, United States.

Nicole P Beyer (NP)

Weill Cornell Medicine, New York, NY, United States.

Georgia Vasilopoulos (G)

Weill Cornell Medicine, New York, NY, United States.

Kellie A Woll (KA)

University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Adam C Hall (AC)

Smith College, Northampton, MA, United States.

Roderic G Eckenhoff (RG)

University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.

Dipti N Barman (DN)

Weill Cornell Medicine, New York, NY, United States.

J David Warren (JD)

Weill Cornell Medicine, New York, NY, United States.

Gareth R Tibbs (GR)

Weill Cornell Medicine, New York, NY, United States. Electronic address: tibbsga@med.cornell.edu.

Peter A Goldstein (PA)

Weill Cornell Medicine, New York, NY, United States.

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Classifications MeSH

questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence d'acides aminés › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Eucaryotes › Animaux › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux contrôlés par les nucléotides cycliques et activés par l'hyperpolarisation › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes électrophysiologiques › Ouverture et fermeture des portes des canaux ioniques › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Cellules › Cellules germinales › Ovocytes › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Phénols › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Alkylphenol inverse agonists of HCN1 gating:...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Amphibiens › Anura › Pipidae › Xenopus › Xenopus laevis › Alkylphenol inverse agonists of HCN1 gating:...