Synthesis and structure-activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor

Silva, Ro
de Oliveira, As
Nunes Lemes, Lf
de Camargo Nascente, L
Coelho do Nascimento Nogueira, P
Silveira, Er
Brand, Gd
Vistoli, G
Cilia, A
Poggesi, E
BUCCIONI, Michela
MARUCCI, Gabriella
Bolognesi, Ml
Romeiro, La

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Publication date

January 2016

DOI

10.1016/j.ejmech.2016.06.052

ISSN

0223-5234

Abstract

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar ...