title: Affinity and activity profiling of unichiral 8-substituted 1,4-benzodioxane analogues of WB4101 reveals a potent and selective α1B-adrenoceptor antagonist.
abstract: Unichiral 8-substituted analogues of 2-[(2-(2,6-dimethoxyphenoxy)ethyl)aminomethyl]-1,4-benzodioxane (WB4101) were synthesized and tested for binding affinity at cloned human α(1a)-, α(1b)-and α(1d)-adrenoreceptor (α(1a)-, α(1b)-and α(1d)-AR) and at native rat 5-HT(1A) receptor and for antagonist affinity at α(1A)-, α(1B)-and α(1D)-AR and at α(2A/D)-AR. Among the selected 8-substituents, namely fluorine, chlorine, methoxyl and hydroxyl, only the last caused significant decrease of α(1) binding affinity in comparison with the lead compound. Functional tests on the S isomers confirmed the detrimental effect of OH positioned in proximity to benzodioxane O(1). For the other three substituents (F, Cl, OMe), the α(1A) and the α(1D) antagonist affinities were generally lower than the α(1a) and α(1d) binding affinities, but not the α(1B) antagonist affinity, which was similar and sensibly higher compared to α(1b) binding affinity in the case of F and OMe respectively. This trend confers significant α(1B)-AR selectivity, in particular, to the 8-methoxy analogue of (S)-WB4101, a new potent (pA(2) 9.58) α(1B)-AR antagonist. The S enantiomers of all the tested compounds were proved to act as α(1)-AR inverse agonists in a vascular model.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Milano, via Mangiagalli 25, I-20133 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: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.forename: Michael
authors.initials: M
authors.lastname: Zagami
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiodini
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; D044263:Receptors, Serotonin, 5-HT1; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D002118:Calcium