title: Synthesis and alpha(1)-adrenoceptor antagonist activity of derivatives and isosters of the furan portion of (+)-cyclazosin.
abstract: alpha(1)-Adrenoceptor selective antagonists are crucial in investigating the role and biological functions of alpha(1)-adrenoceptor subtypes. We synthesized and studied the alpha(1)-adrenoceptor blocking properties of new molecules structurally related to the alpha(1B)-adrenoceptor selective antagonist (+)-cyclazosin, in an attempt to improve its receptor selectivity. In particular, we investigated the importance of substituents introduced at position 5 of the 2-furan moiety of (+)-cyclazosin and its replacement with classical isosteric rings. The 5-methylfuryl derivative (+)-3, [(+)-metcyclazosin], improved the pharmacological properties of the progenitor, displaying a competitive antagonism and an 11 fold increased selectivity for alpha(1B) over alpha(1A), while maintaining a similar selectivity for the alpha(1B)-adrenoceptor relative to the alpha(1D)-adrenoceptor. Compound (+)-3 may represent a useful tool for alpha(1B)-adrenoceptor characterization in functional studies.
authors.affiliation: Department of Chemical Sciences, University of Camerino, 62032 Camerino, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sagratini
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Ugo
authors.initials: U
authors.lastname: Gulini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
authors.forename: Amedeo
authors.initials: A
authors.lastname: Leonardi
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.forename: Dario
authors.initials: D
authors.lastname: Giardinà
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001667:Binding, Competitive; D005663:Furans / Q000737:chemistry*; D008297:Male; D015394:Molecular Structure; D011224:Prazosin / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013154:Spleen / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D005663:Furans; D011799:Quinazolines; D011810:Quinoxalines; D018340:Receptors, Adrenergic, alpha-1; C080462:cyclazosin; C039281:furan; D011224:Prazosin