title: WB4101-related compounds: new, subtype-selective alpha1-adrenoreceptor antagonists (or inverse agonists?).
abstract: Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, viale Abruzzi 42, I-20131 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Ugenti
authors.forename: Simona
authors.initials: S
authors.lastname: Colleoni
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009928:Organ Specificity; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D058668:Adrenergic alpha-1 Receptor Antagonists; D001713:Biphenyl Compounds; D004146:Dioxanes; D008744:Methylamines; D013764:Tetrahydronaphthalenes; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane