Document Detail

Structure-antigastrin activity relationships of new spiroglumide amido acid derivatives.
MedLine Citation:
PMID:  8568800     Owner:  NLM     Status:  MEDLINE    
A series of new spiroglumide amido acid derivatives was synthesized and evaluated for their ability to inhibit the binding of cholecystokinin (CCK) to guinea pig brain cortex (CCKB receptors) and peripheral rat pancreatic acini (CCKA receptors), as well as to inhibit in vitro the gastrin-induced Ca2+ increase in rabbit gastric parietal cells. Appropriate chemical manipulations of the structure of spiroglumide (CR 2194), i.e., (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid, led to potent and selective antagonists of CCKB/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives, as, for example, compound 54 (CR 2622), i.e., (S)-4-[[(R)-4'-[(3,5-dichlorobenzoyl)-amino]-5'-(8- azaspiro[4.5]decan-8-yl)-5'-oxo-pentanoyl]amino]-5- (1-naphthylamino)-5-oxopentanoic acid, exhibit activity 70-170 times greater than that of spiroglumide, depending upon the model used (IC50 = 2 x 10(-8) vs 140 x 10(-8) mol in binding inhibition of [3H]-N-Me-N-Leu-CCK-8 in guinea pig brain cortex and IC50 = 0.7 x 10(-8) vs 122.3 x 10(-8) mol in inhibition of gastrin-induced Ca2+ mobilization in parietal cells of rabbit, respectively). Computer-assisted conformational analysis studies were carried out in order to compare the chemical structure of both the agonist (pentagastrin) and the antagonist (54).
F Makovec; W Peris; S Frigerio; R Giovanetti; O Letari; L Mennuni; L Revel
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  39     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1996 Jan 
Date Detail:
Created Date:  1996-03-01     Completed Date:  1996-03-01     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  135-42     Citation Subset:  IM    
Rotta Research Laboratorium, Milano, Italy.
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MeSH Terms
Anti-Ulcer Agents / chemical synthesis,  pharmacology
Binding, Competitive
Brain / drug effects,  metabolism
Cholecystokinin / antagonists & inhibitors*,  metabolism
Computer-Aided Design
Drug Design
Gastrins / pharmacology
Glutamine / analogs & derivatives*,  chemistry,  pharmacology
Guinea Pigs
Molecular Conformation
Molecular Structure
Pancreas / drug effects,  metabolism
Pentagastrin / pharmacology
Piperidines / chemical synthesis*,  chemistry,  pharmacology*
Rats, Sprague-Dawley
Receptors, Cholecystokinin / antagonists & inhibitors*,  metabolism
Spiro Compounds / chemical synthesis*,  chemistry,  pharmacology*
Stomach / drug effects,  metabolism
Structure-Activity Relationship
Reg. No./Substance:
0/Anti-Ulcer Agents; 0/Gastrins; 0/Piperidines; 0/Receptors, Cholecystokinin; 0/Spiro Compounds; 5534-95-2/Pentagastrin; 56-85-9/Glutamine; 9011-97-6/Cholecystokinin

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