Department of Anesthesiology

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

TitleAlkylphenol inverse agonists of HCN1 gating: H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency.
Publication TypeJournal Article
Year of Publication2019
AuthorsJoyce RL, Beyer NP, Vasilopoulos G, Woll K, Hall AC, Eckenhoff RG, Barman DN, J Warren D, Tibbs GR, Goldstein PA
JournalBiochem Pharmacol
Date Published2019 Feb 13
ISSN1873-2968
Abstract

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 loss of potency with little or no disruption of efficacy. Substitution of compact alkyl groups (iso-propyl, tert-butyl) with shorter (ethyl, methyl) or more extended (sec-butyl) adducts disrupts both potency and efficacy. Ring saturation (with the obligate loss of both planarity and π electrons) primarily disrupts efficacy.

CONCLUSIONS AND IMPLICATIONS: A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å. Within this, a relatively static (with respect to ligand) H-bond donor contributes to initial binding with little involvement in generation of coupling energy. The influence of π electrons/ring planarity and alkyl adducts on efficacy reveals these aspects of the ligand present towards a face of the channel that undergoes structural changes during opening. The site's characteristics suggest it is "druggable"; introduction of other adducts on the ring may generate higher potency inverse agonists.

DOI10.1016/j.bcp.2019.02.013
Alternate JournalBiochem. Pharmacol.
PubMed ID30768926