Synthesis and evaluation of xanomeline analogs-Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor

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27 Citations (Scopus)

Abstract

A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.

Original languageEnglish (US)
Pages (from-to)1376-1392
Number of pages17
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number3
DOIs
StatePublished - Feb 1 2008

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xanomeline
Muscarinic Receptors
Hydrophobic and Hydrophilic Interactions
Binding Sites
Ligands

Keywords

  • Alzheimer's disease
  • Drug design
  • Long-acting
  • M receptor
  • Muscarinic
  • Plasmalemma diffusion microkinetic model
  • Wash-resistant binding
  • Xanomeline

Cite this

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title = "Synthesis and evaluation of xanomeline analogs-Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor",
abstract = "A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.",
keywords = "Alzheimer's disease, Drug design, Long-acting, M receptor, Muscarinic, Plasmalemma diffusion microkinetic model, Wash-resistant binding, Xanomeline",
author = "Kane, {Brian E.} and Grant, {Marianne K.O.} and El-Fakahany, {Esam E} and Ferguson, {David M}",
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T1 - Synthesis and evaluation of xanomeline analogs-Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor

AU - Kane, Brian E.

AU - Grant, Marianne K.O.

AU - El-Fakahany, Esam E

AU - Ferguson, David M

PY - 2008/2/1

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N2 - A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.

AB - A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.

KW - Alzheimer's disease

KW - Drug design

KW - Long-acting

KW - M receptor

KW - Muscarinic

KW - Plasmalemma diffusion microkinetic model

KW - Wash-resistant binding

KW - Xanomeline

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