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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 M(1) muscarinic acetylcholine receptor (M(1) 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 M(1) receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M(1) 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 M(1) 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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Kane BE,Grant MK,El-Fakahany EE,Ferguson DM

doi

10.1016/j.bmc.2007.10.058

subject

Has Abstract

pub_date

2008-02-01 00:00:00

pages

1376-92

issue

3

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(07)00928-5

journal_volume

16

pub_type

杂志文章

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