Opposite vascular activity of (R)-apomorphine and its oxidised derivatives. Endothelium-dependent vasoconstriction induced by the auto-oxidation metabolite.
We have synthetised a series of oxidised apomorphine derivatives (orto and para quinones 2-5), in order to analyse their vascular activity. We have performed radioligand binding assays on rat cortical membranes and functional studies on rat aortic rings. Instead the relaxant activity exhibited by (R)-apomorphine, o-quinones 2, 4, show contractile activity dependent on endothelium in rat aortic rings. Compound 2, the main metabolite of (R)-apomorphine auto-oxidation, was the product which showed enhanced contractile activity by a complex mechanism related to activation of Ca(2+) channels through release and/or inhibition of endothelial factors. Moreover, this compound disrupts the endothelial function as shows the lack of response to acetylcholine observed in vessels pretreated with it.
Abarca
Belén
B
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, Avda. Vicente Andrés Estellés s/n, 460100 Burjassot, Valencia, Spain. belen.abarca@uv.es
Ballesteros
Rafael
R
Bielsa
Patricia
P
Moragues
Juan
J
D'Ocon
Pilar
P
García-Zaragozá
Eugenia
E
Noguera
M Antonia
MA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001058:Apomorphine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D011809:Quinones; D011942:Receptors, Adrenergic, alpha; D011963:Receptors, GABA-A; D014662:Vasoconstrictor Agents; D019001:Nitric Oxide Synthase; D001058:Apomorphine; D000109:Acetylcholine