Document Detail


Structural modifications to tetrahydropyridine-3-carboxylate esters en route to the discovery of M5-preferring muscarinic receptor orthosteric antagonists.
MedLine Citation:
PMID:  23379472     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The M5 muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M5-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M5 over M1 receptor and shows little activity at M2-M4. This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M5 receptor, is potent (IC50 = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M5 receptor based on the crystal structure of the rat M3 receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor.
Authors:
Guangrong Zheng; Andrew M Smith; Xiaoqin Huang; Karunai L Subramanian; Kiran B Siripurapu; Agripina Deaciuc; Chang-Guo Zhan; Linda P Dwoskin
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-18
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-07-11     Completed Date:  2013-07-31     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1693-703     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
CHO Cells
Corpus Striatum / drug effects,  metabolism
Cricetinae
Cricetulus
Dopamine / metabolism
Esters
Humans
Molecular Docking Simulation
Muscarinic Agonists / pharmacology
Oxotremorine / pharmacology
Pyridines / chemical synthesis*,  chemistry,  pharmacology
Radioligand Assay
Rats
Receptor, Muscarinic M5 / antagonists & inhibitors*
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
DA025948/DA/NIDA NIH HHS; DA030667/DA/NIDA NIH HHS; DA05312/DA/NIDA NIH HHS; P50 DA005312/DA/NIDA NIH HHS; R03 DA025948/DA/NIDA NIH HHS; R21 DA030667/DA/NIDA NIH HHS; TR000117/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/Esters; 0/Muscarinic Agonists; 0/Pyridines; 0/Receptor, Muscarinic M5; 5RY0UWH1JL/Oxotremorine; VTD58H1Z2X/Dopamine
Comments/Corrections

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