PT  - JOURNAL ARTICLE
AU  - Jéssica B. Nascimento-Viana
AU  - Aline R. Carvalho
AU  - Luiz Eurico Nasciutti
AU  - Rocío Alcántara-Hernández
AU  - Fernanda Chagas-Silva
AU  - Pedro A. R. Souza
AU  - Luiz Antonio S. Romeiro
AU  - J. Adolfo García-Sáinz
AU  - François Noël
AU  - Claudia Lucia Martins Silva
TI  - New Multi-target Antagonists of <em>α</em><sub>1A-</sub>, <em>α</em><sub>1D-</sub>Adrenoceptors and 5-HT<sub>1A</sub> Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure
AID  - 10.1124/jpet.115.227066
DP  - 2016 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 212--222
VI  - 356
IP  - 1
4099  - http://jpet.aspetjournals.org/content/356/1/212.short
4100  - http://jpet.aspetjournals.org/content/356/1/212.full
SO  - J Pharmacol Exp Ther2016 Jan 01; 356
AB  - Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with α1A-adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of α1D-adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT)1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on- or off-target receptors. LDTs’ potency was estimated in intracellular Ca2+ elevation assays using cells overexpressing human α1-adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs’ effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of α1A-, α1D-adrenoceptors, and 5-HT1A receptors (Ki values in the nanomolar range), and fully inhibited phenylephrine- and 5-HT–induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED50 of 0.15 and 0.09 μg.kg−1, respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment.