title: Pharmacological characterization of N1-(2-methoxyphenyl)-N4-hexylpiperazine as a multi-target antagonist of α1A/α1D-adrenoceptors and 5-HT1A receptors that blocks prostate contraction and cell growth.
abstract: 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 α1A-adrenoceptor blockers, but in several cases monotherapy has failed. Recent studies of prostate pathophysiology have noted the role of α1D-adrenoceptors and 5-HT1A receptors in prostate cell proliferation in addition to the usual role of α1A-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 B values of 3.4 and 2.2 nM for α1A- and α1D-adrenoceptors, respectively. According to the functional binding assays data, LDT66 showed a high affinity (nanomolar range) for the 5-HT1A receptors, behaving as an antagonist. LDT66 also showed a low affinity (micromolar range) for receptors unrelated to BPH such as α1B-adrenoceptors, α2A-adrenoceptors, muscarinic and 5-HT2A receptors, which is a desirable profile in order to prevent putative side effects. Accordingly, LDT66 (100 μg/kg) showed a marginal hypotensive effect. Using the DU-145 prostate cells, control experiments characterized the α1D-adrenoceptor- and 5-HT1A 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.
authors.affiliation: Laboratory of Molecular and Biochemical Pharmacology, Universidade Federal do Rio de Janeiro, Av Carlos Chagas Filho, 373. room J-17, 21941-599, Cidade Universitária, Rio de Janeiro, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Chagas-Silva
authors.forename: Jéssica Barbosa
authors.initials: JB
authors.lastname: Nascimento-Viana
authors.forename: Luiz Antonio S
authors.initials: LA
authors.lastname: Romeiro
authors.forename: Luana C
authors.initials: LC
authors.lastname: Barberato
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.forename: Claudia Lucia Martins
authors.initials: CL
authors.lastname: Silva
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D059411:Lower Urinary Tract Symptoms / Q000188:drug therapy; D008297:Male; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; C000592546:N1-(2-methoxyphenyl)-N4-hexylpiperazine; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D010656:Phenylephrine