Pharmacological characterization of N1-(2-methoxyphenyl)-N4-hexylpiperazine as a multi-target antagonist of [alpha]^sub 1A^/[alpha]^sub 1D^-adrenoceptors and 5-HT^sub 1A^ receptors that blocks prostate contraction and cell growth

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2014-03, Vol.387 (3), p.225
• Main Authors: Chagas-silva, Fernanda, Nascimento-viana, Jéssica Barbosa, Romeiro, Luiz Antonio, S, Barberato, Luana C, Noël, François, Silva, Claudia Lucia, Martins
• Format: Article
• Language: English
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-013-0935-3

Benign prostatic hyperplasia (BPH) is a progressive disease related to the imbalance of cell growth and apoptosis, and it plays a key role in the development of lower urinary tract symptoms (LUTS). The main pharmacological treatment is based on [alpha]^sub 1A^-adrenoceptor blockers, but in several cases monotherapy has failed. Recent studies of prostate pathophysiology have noted the role of [alpha]^sub 1D^-adrenoceptors and 5-HT^sub 1A^ receptors in prostate cell proliferation in addition to the usual role of [alpha]^sub 1A^-adrenoceptors in prostate contraction. N-phenylpiperazine is a scaffold structure that may confer drug affinity for these three receptors. Therefore, the present work aimed to investigate the pharmacological characteristics of N1-(2-methoxyphenyl)-N4-hexylpiperazine (LDT66). Using isometric contraction assays with rat prostate and aorta, LDT66 reduced phenylephrine-induced contractions and showed K ^sub B^ values of 3.4 and 2.2 nM for [alpha]^sub 1A^- and [alpha]^sub 1D^-adrenoceptors, respectively. According to the functional binding assays data, LDT66 showed a high affinity (nanomolar range) for the 5-HT^sub 1A^ receptors, behaving as an antagonist. LDT66 also showed a low affinity (micromolar range) for receptors unrelated to BPH such as [alpha]^sub 1B^-adrenoceptors, [alpha]^sub 2A^-adrenoceptors, muscarinic and 5-HT^sub 2A^ receptors, which is a desirable profile in order to prevent putative side effects. Accordingly, LDT66 (100 [mu]g/kg) showed a marginal hypotensive effect. Using the DU-145 prostate cells, control experiments characterized the [alpha]^sub 1D^-adrenoceptor- and 5-HT^sub 1A^ receptor-mediated cell growth by phenylephrine and 5-HT, respectively. LDT66 (50 nM) prevented both effects similarly. In conclusion, LDT66 is a high-affinity multi-target antagonist of relevant receptors for BPH, and it may be a new starting point for multi-target drug development to treat BPH and LUTS.