Document Detail

Structure-activity relationships in 1,4-benzodioxan-related compounds. 7. Selectivity of 4-phenylchroman analogues for alpha(1)-adrenoreceptor subtypes.
MedLine Citation:
PMID:  11931617     Owner:  NLM     Status:  MEDLINE    
WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (alpha(1A)), vas deferens (alpha(1A)), aorta (alpha(1D)), and spleen (alpha(1B)). In functional assays, compound 5 was the most potent at alpha(1D)-ARs with a reversed selectivity profile (alpha(1D) > alpha(1A) > alpha(1B)) relative to both prototype 1 and phendioxan (2) (alpha(1A) > alpha(1D) > alpha(1B)), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at alpha(1A)-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum alpha(1)-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward alpha(1d/D)-ARs.
Wilma Quaglia; Maria Pigini; Alessandro Piergentili; Mario Giannella; Francesco Gentili; Gabriella Marucci; Antonio Carrieri; Angelo Carotti; Elena Poggesi; Amedeo Leonardi; Carlo Melchiorre
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  45     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2002 Apr 
Date Detail:
Created Date:  2002-04-04     Completed Date:  2002-05-06     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:  1633-43     Citation Subset:  IM    
Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
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MeSH Terms
Adrenergic alpha-Antagonists / chemical synthesis*,  chemistry,  pharmacology
Aorta, Thoracic / drug effects,  physiology
CHO Cells
Chromans / chemical synthesis*,  chemistry,  pharmacology
Dioxanes / chemical synthesis*,  chemistry,  pharmacology
Hela Cells
Models, Molecular
Muscle Contraction / drug effects
Muscle, Smooth / drug effects,  physiology
Prostate / drug effects,  physiology
Radioligand Assay
Rats, Wistar
Receptors, Adrenergic, alpha-1 / drug effects*,  metabolism
Receptors, Serotonin / metabolism
Receptors, Serotonin, 5-HT1
Spleen / drug effects,  physiology
Structure-Activity Relationship
Vas Deferens / drug effects,  physiology
Reg. No./Substance:
0/Adrenergic alpha-Antagonists; 0/Chromans; 0/Dioxanes; 0/Receptors, Adrenergic, alpha-1; 0/Receptors, Serotonin; 0/Receptors, Serotonin, 5-HT1

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