Synthesis of Some Novel Organic Nitrates and Comparative in Vitro Study of Their Vasodilator Profile
journal contributionposted on 09.07.2009, 00:00 authored by Konstantin Chegaev, Loretta Lazzarato, Paolo Marcarino, Antonella Di Stilo, Roberta Fruttero, Nicolas Vanthuyne, Christian Roussel, Alberto Gasco
Synthesis and structural characterization of the 4-phenylbutane-1,2-diyl dinitrate and of the erythro and threo diastereoisomers of 4-phenylbutane-1,2,3-triyl trinitrate as well as the HPLC chiral separation of the corresponding racemic mixtures are reported. Vasodilator activity of the single enantiomers of these products, of 4-phenylbutyl nitrate, and of the previously described phenylpropyl analogues were assessed on rat aorta strips precontracted with phenylephrine. The compounds were able to relax the contracted tissue in a concentration dependent manner. In the couples of antipodes, a complete lack of enantioselectivity was observed as far as the vasodilator potency is concerned. The concentration response curves of the products, with the exception of those of all the trinitrooxy substituted models, were rightward shifted in the presence of ALDH-2 inhibitors. Mono and dinitrates, but not trinitrates, displayed in vitro cross-tolerance with GTN. This new series of nitric acid esters is an interesting tool that can help to shed light on the unresolved puzzle of nitrate pharmacology. Selected members are worthy of additional study as potential drugs.
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enantioselectivityphenylpropyl analoguesNovel Organic NitratespresenceALDHMonocouplecompoundtrinitrateracemic mixturesthreo diastereoisomersseriesVitro StudyphenylbutanelackVasodilator ProfileSynthesisantipodeserythrophenylbutylvasodilator potencycharacterizationpuzzlephenylephrineenantiomernitric acid esterstoolGTNrat aorta strips precontractedexceptionComparativeinhibitornitrate pharmacologyconcentration response curvestissuemannerdinitrateSelected membersVasodilator activityHPLC chiral separationtrinitrooxymodel