title: Synthesis and alpha-adrenoreceptor blocking properties of phenoxybenzamine-related (2-chloroethyl)-(2,3-dihydrobenzo[1,4]dioxin- 2-ylmethyl)-(2-phenoxyethyl) amines.
abstract: A series of beta-chloroethylamines, structural hybrids of WB 4101, a competitive alpha 1-adrenoreceptor antagonist, and phenoxybenzamine, an irreversible alpha-adrenoreceptor antagonist, has been synthesized and tested in isolated rat vas deferens alpha-adrenoreceptors. Although, for all compounds, apparent blocking potency and alpha 1-selectivity are quite similar to those of phenoxybenzamine, affinity values calculated by taking into account the actual concentration of aziridinium ion in solution, reveal that compounds bearing a 1,4-benzodioxan-2-ylmethyl moiety, display a significantly higher potency for both alpha 1- and alpha 2-adrenoreceptors than compounds having a benzyl group. In addition, two of the compounds, having both methyl and methoxy groups in their structure, show a marked discontinuity in the alpha 1-adrenoreceptor concentration-inhibition curve, with a plateau in the range 30-100 nM. Stereochemical aspects are also shown to play an important role in the binding. The biological results suggest that the two irreversible antagonists may be able to discriminate between two alpha 1-adrenoreceptor subtypes, which are both involved in the noradrenaline-induced contraction of the epididymal portion of rat vas deferens.
authors.affiliation: Department of Chemical Sciences, University of Camerino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Giardinà
authors.forename: M
authors.initials: M
authors.lastname: Crucianelli
authors.forename: G
authors.initials: G
authors.lastname: Marucci
authors.forename: F
authors.initials: F
authors.lastname: Paparelli
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D004146:Dioxanes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010643:Phenoxybenzamine / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D001596:Benzylamines; D004146:Dioxanes; D005021:Ethylamines; D010643:Phenoxybenzamine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane