Search for alpha 1-adrenoceptor subtypes selective antagonists: design, synthesis and biological activity of cystazosin, an alpha 1D-adrenoceptor antagonist.
Two novel quinazolines (2 and 3) related to both prazosin and its open analogue 1 were synthesized, and their biological profile at alpha 1-adrenoceptor subtypes was assessed by functional assays in rat isolated tissues, namely prostatic vas deferens (alpha 1A), spleen (alpha 1B) and aorta (alpha 1D). Furthermore, the binding profile of 3 was assessed at native alpha 2 and D2 receptors, and cloned human 5-HT1A receptors, in comparison to prazosin, (+)-cyclazosin, 1 and BMY 7383. It turned out that the cystamine-bearing quinazoline 3 (cystazosin) has a reversed affinity profile relative to (+)-cyclazosin owing to a higher affinity for alpha 1D-adrenoceptors and a significantly lower affinity for the alpha 1A and alpha 1B subtypes. Furthermore, in comparison to BMY 7378, cystazosin (3) displays a much better specificity profile since it has lower affinity for D2 and 5-HT1A receptors.
Minarini
A
A
Department of Pharmaceutical Sciences, University of Bologna, Italy.
Budriesi
R
R
Chiarini
A
A
Leonardi
A
A
Melchiorre
C
C
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013154:Spleen / Q000187:drug effects; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
C547719:ADRA1D protein, human; C547721:Adra1d protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D011799:Quinazolines; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C080462:cyclazosin