title: 6-methoxy-7-benzofuranoxy and 6-methoxy-7-indolyloxy analogues of 2-[2-(2,6-Dimethoxyphenoxy)ethyl]aminomethyl-1,4-benzodioxane (WB4101):1 discovery of a potent and selective α1D-adrenoceptor antagonist.
abstract: Previous results have shown that replacement of one of the two o-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, α1-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α1D-AR antagonist affinity. Such observations inspired the design of four new analogues of 1 bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of 1, the S enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest α1D-AR antagonist affinity (pA2 9.58) with significant α1D/α1A and α1D/α1B selectivity. In addition, compared both to α1D-AR antagonists structurally related to 1 and to the well-known α1D-AR antagonist BMY7378, this derivative had modest 5-HT1A affinity and neutral α1-AR antagonist behavior.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiodini
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Paola
authors.initials: P
authors.lastname: Laurino
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004146:Dioxanes / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane