1,3-dioxolane-based ligands as a novel class of alpha1-adrenoceptor antagonists.
1,3-Dioxolane-based compounds (2-14) were synthesized, and the pharmacological profiles at alpha(1)-adrenoceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)), and aorta (alpha(1D)). Compound 9, with a pA(2) of 7.53, 7.36, and 8.65 at alpha(1A), alpha(1B), and alpha(1D), respectively, is the most potent antagonist of the series, while compound 10 with a pA(2) of 8.37 at alpha(1D) subtype and selectivity ratios of 162 (alpha(1D)/alpha(1A)) and 324 (alpha(1D)/alpha(1B)) is the most selective. Binding assays in CHO cell membranes expressing human cloned alpha(1)-adrenoceptor subtypes confirm the pharmacological profiles derived from functional experiments, although the selectivity values are somewhat lower. Therefore, it is concluded that 1,3-dioxolane-based ligands are a new class of alpha(1)-adrenoceptor antagonists.
Brasili
Livio
L
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, Italy. brasili.livio@unimore.it
Sorbi
Claudia
C
Franchini
Silvia
S
Manicardi
Massimo
M
Angeli
Piero
P
Marucci
Gabriella
G
Leonardi
Amedeo
A
Poggesi
Elena
E
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D004148:Dioxolanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C473677:4-(2-(2-methoxyphenoxy)ethylaminomethyl)-2,2-diphenyl(1,3)dioxolane; C473678:4-(2-phenoxyethylaminomethyl)-2,2-diphenyl(1,3)dioxolane; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D058671:Adrenergic beta-1 Receptor Antagonists; D004148:Dioxolanes; D008024:Ligands