New Multi-target Antagonists of α1A-, α1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure.
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 Ca(2+) 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.
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Jéssica B
JB
Nascimento-Viana
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Aline R
AR
Carvalho
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Luiz Eurico
LE
Nasciutti
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Rocío
R
Alcántara-Hernández
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Fernanda
F
Chagas-Silva
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Pedro A R
PA
Souza
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
Luiz Antonio S
LA
Romeiro
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
J Adolfo
JA
García-Sáinz
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.).
François
F
Noël
Laboratory of Molecular and Biochemical Pharmacology (J.B.N.-V., A.R.C., F.C.-S., F.N., C.L.M.S.) and Cell Biology and Development Research Program (P.A.R.S., L.E.N.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Cell Physiology Institute, Universidad Nacional Autónoma de México, D.F., Mexico (R.A.-H., J.A.G.-S.); and Pharmaceutical Sciences, Universidade de Brasília, Brasília, Brazil (L.A.S.R.) silva.claudiamartins.ufrj@gmail.com cmartins@farmaco.ufrj.br.
Claudia Lucia Martins
CL
Silva
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D014521:Urethra / Q000187:drug effects* / Q000502:physiology
D058668:Adrenergic alpha-1 Receptor Antagonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D010656:Phenylephrine; D012701:Serotonin