Document Detail

3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines: opioid antagonists with potent anorectant activity.
MedLine Citation:
PMID:  8410999     Owner:  NLM     Status:  MEDLINE    
A series of (3R*,4R*)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated for their effect on food consumption in obese Zucker rats. Opioid affinity (mu, kappa, and delta for selected compounds) and opioid antagonist activity (mu and kappa) were characterized and compared to effects on food consumption. No compounds with high selectivity for either mu or kappa receptors were discovered. However, compounds in the series had exceptional potency as opioid antagonists and in reducing food consumption in the obese Zucker rat. In contrast, a few compounds with high potency as opioid antagonists had much weaker potency for inhibiting food consumption. (3R,4R)-3,4-Dimethyl-1-[(3S)-3- hydroxy-3-cyclohexyl-propyl]-4-(3-hydroxyphenyl)piperidine (11,LY255582) emerged as having the best activity profile, both in reducing food consumption and as an opioid antagonist. Compound 11 is a highly potent mu, kappa-, and delta-opioid antagonist with possible clinical utility as an appetite suppressant for weight loss.
C H Mitch; J D Leander; L G Mendelsohn; W N Shaw; D T Wong; B E Cantrell; B G Johnson; J K Reel; J D Snoddy; A E Takemori
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  36     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1993 Oct 
Date Detail:
Created Date:  1993-11-09     Completed Date:  1993-11-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2842-50     Citation Subset:  IM    
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
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MeSH Terms
Appetite Depressants / chemistry,  metabolism,  pharmacology*
Cyclohexanes / chemistry,  metabolism,  pharmacology*
Diuresis / drug effects
Eating / drug effects
Endorphins / antagonists & inhibitors*
Guinea Pigs
Molecular Structure
Piperidines / chemistry,  metabolism,  pharmacology*
Rats, Sprague-Dawley
Rats, Zucker
Receptors, Opioid, delta / antagonists & inhibitors,  physiology
Receptors, Opioid, kappa / antagonists & inhibitors,  physiology
Receptors, Opioid, mu / antagonists & inhibitors,  physiology
Structure-Activity Relationship
Reg. No./Substance:
0/Appetite Depressants; 0/Cyclohexanes; 0/Endorphins; 0/Piperidines; 0/Receptors, Opioid, delta; 0/Receptors, Opioid, kappa; 0/Receptors, Opioid, mu; 120938-72-9/LY 243670

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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