title: Synthesis and structure-activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor.
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.
authors.affiliation: 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.
authors.forename: Renata Oliveira
authors.initials: RO
authors.lastname: Silva
authors.affiliation: 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.
authors.forename: Andressa Souza
authors.initials: AS
authors.lastname: de Oliveira
authors.affiliation: LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
authors.forename: Laís Flávia
authors.initials: LF
authors.lastname: Nunes Lemes
authors.affiliation: LADETER, Catholic University of Brasília, QS 07, Lote 01, EPCT, Águas Claras, 71966-700, Brasília, DF, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: de Camargo Nascente
authors.affiliation: Departament of Organic and Inorganic Chemistry, Federal University of Ceará, 60021-970, Fortaleza, CE, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Coelho do Nascimento Nogueira
authors.affiliation: Departament of Organic and Inorganic Chemistry, Federal University of Ceará, 60021-970, Fortaleza, CE, Brazil.
authors.forename: Edilberto R
authors.initials: ER
authors.lastname: Silveira
authors.affiliation: Chemistry Institute, University of Brasília, Campus Universitário Darcy Ribeiro, 70910-900, Brasília, DF, Brazil.
authors.forename: Guilherme D
authors.initials: GD
authors.lastname: Brand
authors.affiliation: Department of Pharmaceutical Science, University of Milan, Via Mangiagalli 25, 20133, Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.affiliation: Drug Discovery Department, Recordati S.p.A, Via Civitali 1, 20148, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cilia
authors.affiliation: Drug Discovery Department, Recordati S.p.A, Via Civitali 1, 20148, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Poggesi
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, I-62032, Camerino, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, I-62032, Camerino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: marialaura.bolognesi@unibo.it.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.affiliation: 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.
authors.forename: Luiz Antonio Soares
authors.initials: LAS
authors.lastname: Romeiro
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1
keywords: Adrenergic receptors subtypes; Arylpiperazines; BPH; α(1)-Adrenergic antagonists