Format

Send to

Choose Destination
Eur J Med Chem. 2016 Oct 21;122:601-610. doi: 10.1016/j.ejmech.2016.06.052. Epub 2016 Jun 30.

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

Author information

1
Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
2
LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
3
Departament of Organic and Inorganic Chemistry, Federal University of Ceará, 60021-970, Fortaleza, CE, Brazil.
4
Chemistry Institute, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil.
5
Department of Pharmaceutical Science, University of Milan, Via Mangiagalli 25, 20133, Milan, Italy.
6
Drug Discovery Department, Recordati S.p.A, Via Civitali 1, 20148, Milan, Italy.
7
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, I-62032, Camerino, Italy.
8
Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
9
Department of Pharmacy, Health Sciences Faculty, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil; LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil. Electronic address: luizromeiro@unb.br.

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 selectivity could have relevance for a potential LUTS/BPH therapeutic application.

KEYWORDS:

Adrenergic receptors subtypes; Arylpiperazines; BPH; α(1)-Adrenergic antagonists

PMID:
27448917
DOI:
10.1016/j.ejmech.2016.06.052
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center