Document Detail

Studies on agents with mixed NO-dependent and calcium channel antagonistic vasodilating activities.
MedLine Citation:
PMID:  11405285     Owner:  NLM     Status:  MEDLINE    
PURPOSE: To obtain new cardiovascular agents with mixed Ca2+-channel antagonistic and NO-donor properties, a series of "hybrid" 1,4-dihydropyridines (1,4-DHPs), bearing NO-donating furoxan moieties on the 3-positioned lateral ester chain were synthesized and pharmacologically characterized. Furazan analogues were also prepared and investigated for control purposes, because they are unable to release NO. METHODS: Synthesis of the models was achieved by a modified Hantzsch approach. All of the final furoxan 1,4-DHPs were assessed for their ability to produce nitrite in the presence of a large excess of cysteine by the Griess reaction. Vasodilating activity was evaluated on rat aorta and expressed as EC50 and EC50MB values, obtained in the absence and in the presence of methylene blue (MB) respectively, a well-known guanylate cyclase inhibitor. Affinities to 1,4-DHP receptor on Ca2+-channels, expressed as IC50 values, were determined through displacement experiments of [3H]-nitrendipine on rat cortex homogenates. RESULTS: Some hybrid compounds (derivatives 15a, 15b, 16a, and 16b) displayed vasodilating activity depending predominantly on their Ca2+-channel blocker properties. By contrast, some others (derivatives 17a, 17b, and 21) behaved as well-balanced hybrids with mixed Ca2+-channel blocking and NO-dependent vasodilating activities. CONCLUSION: This work demonstrates the possibility of obtaining well-balanced hybrids endowed with mixed NO-donor and Ca2+-channel blocker properties using appropriate 1,4-DHP and furoxan moieties. A procedure for the individual evaluation of the NO-dependent vasodilator component and that due to Ca2+-channel blocking is proposed.
C Cena; S Visentin; A Di Stilo; D Boschi; R Fruttero; A Gasco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmaceutical research     Volume:  18     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-06-14     Completed Date:  2002-01-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  157-65     Citation Subset:  IM    
Dipartimento di Scienza e Tecnologia del Farmaco, Torino, Italy.
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MeSH Terms
Aorta / drug effects,  physiology
Calcium Channel Blockers / chemical synthesis*,  chemistry,  pharmacology
Cardiovascular Agents / chemical synthesis*,  chemistry,  pharmacology
Dihydropyridines / chemical synthesis*,  chemistry,  pharmacology
Dose-Response Relationship, Drug
Nitric Oxide / metabolism*
Nitric Oxide Donors / chemical synthesis*,  chemistry,  pharmacology
Rats, Wistar
Vasodilation / drug effects
Vasodilator Agents / chemical synthesis,  chemistry,  pharmacology
Reg. No./Substance:
0/Calcium Channel Blockers; 0/Cardiovascular Agents; 0/Dihydropyridines; 0/Nitric Oxide Donors; 0/Vasodilator Agents; 10102-43-9/Nitric Oxide; 3337-17-5/1,4-dihydropyridine

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