Synthesis of ranolazine derivatives containing the (1S,4S)-2,5-diazabicyclo[2.2.1]heptane moiety and their evaluation as vasodilating agents.
Two diazabicyclic analogues of ranolazine, (S,S,S)-5 and (S,S,R)-5, and their epimeric mixture were synthesized. Furthermore, their vasomotor effects on rat aorta rings precontracted with phenylephrine were analyzed. These compounds showed vasodilating effects significantly greater than ranolazine. The vasodilating activities of these analogues have two components, one that depends on the endothelium, due to the release of NO, and another one due to a direct effect on the vascular smooth muscle. The compounds [(S,S,S)(S,S,R)]-5 and (S,S,R)-5 induce, in a manner similar to ranolazine, the release of a prostanoid from the cyclooxygenase pathway, whose vasoconstrictor effect is masked by the predominant vasodilation induced by these compounds.
Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México (UNAM), Batalla del 5 de Mayo y Fuerte de Loreto, Iztapalapa, 09230, México, D.F., México.
Manuel
M
López-Ortiz
Ivan
I
Monsalvo
Patricia
P
Demare
Cristina
C
Paredes
Dieter
D
Mascher
Carlos
C
Hernández
Marcos
M
Hernández
Ignacio
I
Regla
D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D006536:Heptanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D000083:Acetanilides; D001372:Aza Compounds; D006536:Heptanes; D010879:Piperazines; D014662:Vasoconstrictor Agents; D000069458:Ranolazine
chemical structure; chirality relationship to biology; drug discovery; ranolazine