Synthesis of some novel organic nitrates and comparative in vitro study of their vasodilator profile.
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.
Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, 10125 Torino, Italy.
Konstantin
K
Chegaev
Loretta
L
Lazzarato
Paolo
P
Marcarino
Antonella
A
Di Stilo
Roberta
R
Fruttero
Nicolas
N
Vanthuyne
Christian
C
Roussel
Alberto
A
Gasco
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors; D009566:Nitrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005996:Nitroglycerin; D010656:Phenylephrine; D051381:Rats; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D024101:Mitochondrial Proteins; D009566:Nitrates; D014665:Vasodilator Agents; D010656:Phenylephrine; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D005996:Nitroglycerin