title: Searching for cyclazosin analogues as alpha(1B)-adrenoceptor antagonists.
abstract: A series of quinazoline derivatives, 2-20, structurally related to the racemic alpha(1)-adrenoceptor antagonist cyclazosin (1), were synthesized and evaluated for their functional antagonism at alpha(1)- and alpha(2)-adrenoceptors and for their binding affinity at human cloned alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptor subtypes. They displayed, like 1, preferential antagonism and selectivity for alpha(1) versus alpha(2)-adrenoceptors. Compounds 10, 13, and 18 showed high potency at alpha(1)-adrenoceptors similar to that of 1 (pK(B) values 8.47-8.89 versus 8.67), whereas 13 and 15 were endowed with the highest alpha(1)-adrenoceptor selectivity, only 3- to 4-fold lower than that of 1. In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1, with the exception of 19 and 20 that were definitely less potent. The s-triazine analogue 18 was the most potent of the series with pK(i) values of 10.15 (alpha(1a)), 10.22 (alpha(1b)) and 10.40 (alpha(1d)), resulting 77-fold more potent than 1 at alpha(1a)-adrenoceptors. In addition, the majority of compounds, like prototype 1, showed the same trend of preferential affinity for alpha(1d)- and alpha(1b)-adrenoceptors that alpha(1a)-subtype. In conclusion, we identified compounds 2-5, 10, 12 and 13, bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S Agostino, 1 62032 Camerino, Italy. dario.giardina@unicam.it
authors.forename: Dario
authors.initials: D
authors.lastname: Giardinà
authors.forename: O
authors.initials: O
authors.lastname: Polimanti
authors.forename: G
authors.initials: G
authors.lastname: Sagratini
authors.forename: P
authors.initials: P
authors.lastname: Angeli
authors.forename: U
authors.initials: U
authors.lastname: Gulini
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
authors.forename: E
authors.initials: E
authors.lastname: Poggesi
authors.forename: A
authors.initials: A
authors.lastname: Leonardi
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001665:Binding Sites / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D016466:CHO Cells / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1; D013154:Spleen / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
chemical_list: C547716:ADRA1B protein, human; D058668:Adrenergic alpha-1 Receptor Antagonists; D011799:Quinazolines; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; C080462:cyclazosin; D011224:Prazosin