title: Novel aryl piperazines for alleviation of 'andropause' associated prostatic disorders and depression.
abstract: A series of seventeen piperazine derivatives have been synthesized and biologically evaluated for the management of andropause-associated prostatic disorders and depression. Five compounds 16, 19, 20, 21 and 22 significantly inhibited proliferation of androgen-sensitive LNCaP prostatic cell line with EC50values of 12.4 μM, 15.6 μM, 11.8 μM, 10.4 μM, 12.2 μM respectively and decreased Ca2+entry through adrenergic-receptor α1Ablocking activity. Anti-androgenic behaviour of compound 19 and 22 was evident by decreased luciferase activity. The high EC50value in AR-negative cells PC3 and DU145 suggested that the cytotoxicity of compounds was due to AR down regulation. Compound 19 reduced the prostate weight of rats by 53.8%. Further, forced-swimming and tail-suspension tests revealed antidepressant-like activity of compound 19, lacking effects on neuromuscular co-ordination. In silico ADMET predictions revealed that the compound 19 had good oral absorption, aqueous solubility, non-hepatotoxic and good affinity for plasma protein binding. Pharmacokinetic and tissue uptake of 19 at 10 mg/kg demonstrated an oral bioavailability of 35.4%. In silico docking studies predicted similar binding pattern of compound 19 on androgen receptor as hydroxyflutamide. Compound 19 appears to be a unique scaffold with promising activities against androgen associated prostatic disorders in males like prostate cancer and BPH and associated depression.
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Pandey
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Shukla
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Singh
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Yadav
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229010, India.
authors.forename: Dilip Kumar
authors.initials: DK
authors.lastname: Tanpula
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli 229010, India.
authors.forename: Surabhi
authors.initials: S
authors.lastname: Singh
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Shubha
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Jawahar
authors.initials: J
authors.lastname: Lal
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: vl_sharma@cdri.res.in.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000726:Androgen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D047649:Andropause; D000818:Animals; D002460:Cell Line; D003863:Depression / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D011469:Prostatic Diseases / Q000188:drug therapy*; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects
chemical_list: D000726:Androgen Antagonists; D010879:Piperazines; D011944:Receptors, Androgen; D000077489:Piperazine
keywords: MTT assay; Pharmacokinetics; Piperazine derivatives; α(1A) blocking activity