Alkylphenol inverse agonists of HCN1 gating : H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency
Copyright © 2019 Elsevier Inc. All rights reserved..
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-1 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 Å3. 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:163 |
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| Enthalten in: |
Biochemical pharmacology - 163(2019) vom: 01. Mai, Seite 493-508 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Joyce, Rebecca L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.01.2020 Date Revised 01.05.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2019.02.013 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM293943524 |
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| 100 | 1 | |a Joyce, Rebecca L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Alkylphenol inverse agonists of HCN1 gating |b H-bond propensity, ring saturation and adduct geometry differentially determine efficacy and potency |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.01.2020 | ||
| 500 | |a Date Revised 01.05.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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) | ||
| 520 | |a EXPERIMENTAL APPROACH: Using in vitro electrophysiology and kinetic modeling, we systematically explore the contribution of ligand architecture to alkylphenol-channel coupling | ||
| 520 | |a 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-1 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 | ||
| 520 | |a CONCLUSIONS AND IMPLICATIONS: A hydrophobicity-independent decrement in potency at higher volumes suggests the alkylbenzene site has a volume of ≥800 Å3. 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 2-Fluoro-13-di-iso-propylbenzene | |
| 650 | 4 | |a Alkylphenol | |
| 650 | 4 | |a Anti-hyperalgesia | |
| 650 | 4 | |a Cyclohexanol | |
| 650 | 4 | |a HCN channels | |
| 650 | 4 | |a Inverse agonists | |
| 650 | 4 | |a Kinetic modeling | |
| 650 | 4 | |a Neuropathic pain | |
| 650 | 4 | |a Phenyl-fluorine | |
| 650 | 4 | |a Phenyl-isocyanate | |
| 650 | 4 | |a Phenyl-thiol | |
| 650 | 4 | |a Propofol | |
| 650 | 7 | |a Hcn1 protein, mouse |2 NLM | |
| 650 | 7 | |a Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels |2 NLM | |
| 650 | 7 | |a Phenols |2 NLM | |
| 650 | 7 | |a Potassium Channels |2 NLM | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 700 | 1 | |a Beyer, Nicole P |e verfasserin |4 aut | |
| 700 | 1 | |a Vasilopoulos, Georgia |e verfasserin |4 aut | |
| 700 | 1 | |a Woll, Kellie A |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Adam C |e verfasserin |4 aut | |
| 700 | 1 | |a Eckenhoff, Roderic G |e verfasserin |4 aut | |
| 700 | 1 | |a Barman, Dipti N |e verfasserin |4 aut | |
| 700 | 1 | |a Warren, J David |e verfasserin |4 aut | |
| 700 | 1 | |a Tibbs, Gareth R |e verfasserin |4 aut | |
| 700 | 1 | |a Goldstein, Peter A |e verfasserin |4 aut | |
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