title: Structure-activity relationships in 1,4-benzodioxan-related compounds. 7. Selectivity of 4-phenylchroman analogues for alpha(1)-adrenoreceptor subtypes.
abstract: WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors. Moreover, their receptor selectivity was further determined in functional experiments in isolated rat prostate (alpha(1A)), vas deferens (alpha(1A)), aorta (alpha(1D)), and spleen (alpha(1B)). In functional assays, compound 5 was the most potent at alpha(1D)-ARs with a reversed selectivity profile (alpha(1D) > alpha(1A) > alpha(1B)) relative to both prototype 1 and phendioxan (2) (alpha(1A) > alpha(1D) > alpha(1B)), whereas compound 8, bearing a carbonyl moiety at position 1, was the most potent at alpha(1A)-ARs with a selectivity profile similar to that of prototypes. The least potent of the series was the trans isomer 6, suggesting that optimum alpha(1)-AR blocking activity in this series is associated with a cis relationship between the 2-side chain and the 4-phenyl ring rather than a trans relationship as previously observed for the 2-side chain and the 3-phenyl ring in 2 and related compounds. Binding affinity results were not in complete agreement with the selectivity profiles deriving from functional experiments. Although a firm explanation was not available, neutral and negative antagonism and receptor dimerization were considered as two possibilities to account for the difference between binding and functional affinities. Finally, compound 5 was selected for a modeling study in comparison with 1, mephendioxan (3), and open phendioxan (4) to achieve information on the physicochemical interactions that account for its high affinity toward alpha(1d/D)-ARs.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Maria
authors.initials: M
authors.lastname: Pigini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piergentili
authors.forename: Mario
authors.initials: M
authors.lastname: Giannella
authors.forename: Francesco
authors.initials: F
authors.lastname: Gentili
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.forename: Amedeo
authors.initials: A
authors.lastname: Leonardi
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000317:Adrenergic alpha-Antagonists; D002839:Chromans; D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1