Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Mini Reviews in Medicinal Chemistry
  4. Volume 25, Issue 1
  5. Article
Volume 25, Issue 1
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs .

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mrmc/10.2174/0113895575319878240612070850
2024-06-18
2024-12-26

  • From This Site

    /content/journals/mrmc/10.2174/0113895575319878240612070850
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. WHO. 2023 Available from: https://www.who.int/news-room/fact-sheets/detail/depression
  2. PengG. TianJ. GaoX. ZhouY. QinX. Research on the pathological mechanism and drug treatment mechanism of depression.Curr. Neuropharmacol.201513451452310.2174/1570159X130415083112042826412071
     [Google Scholar]
  3. RemesO. MendesJ.F. TempletonP. Biological, psychological, and social determinants of depression: A review of recent literature.Brain Sci.202111121633
     [Google Scholar]
  4. PacherP. KohegyiE. KecskemetiV. FurstS. Current trends in the development of new antidepressants.Curr. Med. Chem.2001828910010.2174/092986701337379611172668
     [Google Scholar]
  5. VetulaniJ. NalepaI. Antidepressants: Past, present and future.Eur. J. Pharmacol.20004051-335136310.1016/S0014‑2999(00)00565‑311033340
     [Google Scholar]
  6. HirschfeldR.M. History and evolution of the monoamine hypothesis of depression.J. Clin. Psychiatry200061Suppl. 64610775017
     [Google Scholar]
  7. OwensM.J. Selectivity of antidepressants: From the monoamine hypothesis of depression to the SSRI revolution and beyond.J. Clin. Psychiatry200465Suppl. 451015046536
     [Google Scholar]
  8. JauharS. CowenP.J. BrowningM. Fifty years on: Serotonin and depression.J. Psychopharmacol.202337323724110.1177/0269881123116181336938996
     [Google Scholar]
  9. PannuA. Serotonin and depression: Scrutiny of new targets for future anti- depressant drug development.Curr. Drug Targets20232481683710.2174/138945012466623042523372737170981
     [Google Scholar]
  10. AlbertP.R. Adult neuroplasticity: A new “cure” for major depression?J. Psychiatry Neurosci.201944314715010.1503/jpn.19007231038297
     [Google Scholar]
  11. KrausC. CastrénE. KasperS. LanzenbergerR. Serotonin and neuroplasticity-Links between molecular, functional and structural pathophysiology in depression.Neurosci. Biobehav. Rev.20177731732610.1016/j.neubiorev.2017.03.00728342763
     [Google Scholar]
  12. HongR. LiX. Discovery of monoamine oxidase inhibitors by medicinal chemistry approaches.MedChemComm2019101102510.1039/C8MD00446C30774851
     [Google Scholar]
  13. YamadaM. YasuharaH. Clinical pharmacology of MAO inhibitors: Safety and future.Neurotoxicology2004251-221522110.1016/S0161‑813X(03)00097‑414697896
     [Google Scholar]
  14. BonnetU. Moclobemide: Therapeutic use and clinical studies.CNS Drug Rev.2003919714010.1111/j.1527‑3458.2003.tb00245.x12595913
     [Google Scholar]
  15. WangS.M. HanC. BahkW.M. LeeS.J. PatkarA.A. MasandP.S. PaeC.U. Addressing the side effects of contemporary antidepressant drugs: A comprehensive review.Chonnam Med. J.201854210111210.4068/cmj.2018.54.2.10129854675
     [Google Scholar]
  16. ProttiM. MandrioliR. MarascaC. CavalliA. SerrettiA. MercoliniL. New‐generation, non‐SSRI antidepressants: Drug‐drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others.Med. Res. Rev.20204051794183210.1002/med.2167132285503
     [Google Scholar]
  17. BergerM. GrayJ.A. RothB.L. The expanded biology of serotonin.Annu. Rev. Med.200960135536610.1146/annurev.med.60.042307.11080219630576
     [Google Scholar]
  18. LvJ. LiuF. The role of serotonin beyond the central nervous system during embryogenesis.Front. Cell. Neurosci.2017117410.3389/fnpit.2017.0040028348520
     [Google Scholar]
  19. KanovaM. KohoutP. Tryptophan: A unique role in the critically ill.Int. J. Mol. Sci.2021222111714
     [Google Scholar]
  20. YabutJ.M. CraneJ.D. GreenA.E. KeatingD.J. KhanW.I. SteinbergG.R. Emerging roles for serotonin in regulating metabolism: New implications for an ancient molecule.Endocr. Rev.20194041092110710.1210/er.2018‑0028330901029
     [Google Scholar]
  21. López-MuñozF. AlamoC. Monoaminergic neurotransmission: The history of the discovery of antidepressants from 1950s until today.Curr. Pharm. Des.200915141563158610.2174/13816120978816800119442174
     [Google Scholar]
  22. MoncrieffJ. CooperR.E. StockmannT. AmendolaS. HengartnerM.P. HorowitzM.A. The serotonin theory of depression: A systematic umbrella review of the evidence.Mol. Psychiatry20232883243325610.1038/s41380‑022‑01661‑035854107
     [Google Scholar]
  23. VaswaniM. LindaF.K. RameshS. Role of selective serotonin reuptake inhibitors in psychiatric disorders: A comprehensive review.Prog. Neuropsychopharmacol. Biol. Psychiatry20032718510210.1016/S0278‑5846(02)00338‑X12551730
     [Google Scholar]
  24. DubovickyM. BelovicovaK. CsatlosovaK. BogiE. Risks of using SSRI/SNRI antidepressants during pregnancy and lactation.Interdiscip. Toxicol.2017101303410.1515/intox‑2017‑000430123033
     [Google Scholar]
  25. KhawamE.A. LaurencicG. MaloneD.A.Jr Side effects of antidepressants: An overview.Cleve. Clin. J. Med.2006734351353, 356-36110.3949/ccjm.73.4.35116610395
     [Google Scholar]
  26. MarksS. A clinical review of antidepressants, their sexual side-effects, post-SSRI sexual dysfunction, and serotonin syndrome.Br. J. Nurs.2023321467868210.12968/bjon.2023.32.14.67837495413
     [Google Scholar]
  27. EdinoffA.N. AkulyH.A. HannaT.A. OchoaC.O. PattiS.J. GhaffarY.A. KayeA.D. ViswanathO. UritsI. BoyerA.G. CornettE.M. KayeA.M. Selective serotonin reuptake inhibitors and adverse effects: A narrative review.Neurol. Int.202113338740110.3390/neurolint1303003834449705
     [Google Scholar]
  28. CaspiA. SugdenK. MoffittT.E. TaylorA. CraigI.W. HarringtonH. McClayJ. MillJ. MartinJ. BraithwaiteA. PoultonR. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.Science2003301563138638910.1126/science.108396812869766
     [Google Scholar]
  29. PithadiaA. JainS.M. 5-hydroxytryptamine receptor subtypes and their modulators with therapeutic potentials.J. Clin. Med. Res.200912728010.4021/jocmr2009.05.123722505971
     [Google Scholar]
  30. YohnC.N. GerguesM.M. SamuelsB.A. The role of 5-HT receptors in depression.Mol. Brain20171012810.1186/s13041‑017‑0306‑y28646910
     [Google Scholar]
  31. ArtigasF. BortolozziA. CeladaP. Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies.Eur. Neuropsychopharmacol.201828444545610.1016/j.euroneuro.2017.10.03229174531
     [Google Scholar]
  32. NautiyalK.M. HenR. Serotonin receptors in depression: From A to B.F1000 Res.2017612310.12688/f1000research.9736.1
     [Google Scholar]
  33. LiX. SunX. SunJ. ZuY. ZhaoS. SunX. LiL. ZhangX. WangW. LiangY. WangW. LiangX. SunC. GuanX. TangM. Depressive-like state sensitizes 5-HT1A and 5-HT1B auto-receptors in the dorsal raphe nucleus sub-system.Behav. Brain Res.202038911261810.1016/j.bbr.2020.11261832360167
     [Google Scholar]
  34. SariY. Serotonin receptors: From protein to physiological function and behavior.Neurosci. Biobehav. Rev.200428656558210.1016/j.neubiorev.2004.08.00815527863
     [Google Scholar]
  35. HervásI. QueirozC.M.T. AdellA. ArtigasF. Role of uptake inhibition and autoreceptor activation in the control of 5‐HT release in the frontal cortex and dorsal hippocampus of the rat.Br. J. Pharmacol.2000130116016610.1038/sj.bjp.070329710781012
     [Google Scholar]
  36. KnobelmanD.A. HenR. LuckiI. Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse.J. Pharmacol. Exp. Ther.200129831083109111504805
     [Google Scholar]
  37. BurnetP.W.J. EastwoodS.L. LaceyK. HarrisonP.J. The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain.Brain Res.1995676115716810.1016/0006‑8993(95)00104‑X7796165
     [Google Scholar]
  38. HannonJ. HoyerD. Molecular biology of 5-HT receptors.Behav. Brain Res.2008195119821310.1016/j.bbr.2008.03.02018571247
     [Google Scholar]
  39. MestreT.A. ZurowskiM. FoxS.H. 5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders.Expert Opin. Investig. Drugs201322441142110.1517/13543784.2013.76995723409724
     [Google Scholar]
  40. GawlińskiD. SmagaI. ZaniewskaM. GawlińskaK. Faron-GóreckaA. FilipM. Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors.Pharmacol. Rep.2019716994100010.1016/j.pharep.2019.05.01231546158
     [Google Scholar]
  41. DuxonM.S. FlaniganT.P. ReavleyA.C. BaxterG.S. BlackburnT.P. FoneK.C.F. Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the rat central nervous system.Neuroscience199776232332910.1016/S0306‑4522(96)00480‑09015317
     [Google Scholar]
  42. DiazS.L. DolyS. Narboux-NêmeN. FernándezS. MazotP. BanasS.M. BoutourlinskyK. MoutkineI. BelmerA. RoumierA. MaroteauxL. 5-HT2B receptors are required for serotonin-selective antidepressant actions.Mol. Psychiatry201217215416310.1038/mp.2011.15922158014
     [Google Scholar]
  43. MillanM.J. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: Focus on novel therapeutic strategies.Therapie200560544146010.2515/therapie:200506516433010
     [Google Scholar]
  44. SerratsJ. MengodG. CortésR. Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei.J. Chem. Neuroanat.2005292839110.1016/j.jchemneu.2004.03.01015652696
     [Google Scholar]
  45. GuptaD. PrabhakarV. RadhakrishnanM. 5HT3 receptors: Target for new antidepressant drugs.Neurosci. Biobehav. Rev.20166431132510.1016/j.neubiorev.2016.03.00126976353
     [Google Scholar]
  46. PuigM.V. SantanaN. CeladaP. MengodG. ArtigasF. In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors.Cereb. Cortex200414121365137510.1093/cercor/bhh09715166106
     [Google Scholar]
  47. RedrobeJ.P. BourinM. Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test.Eur. J. Pharmacol.19973252-312913510.1016/S0014‑2999(97)00115‑59163559
     [Google Scholar]
  48. VarnäsK. HalldinC. PikeV.W. HallH. Distribution of 5-HT4 receptors in the postmortem human brain—an autoradiographic study using [125I]SB 207710.Eur. Neuropsychopharmacol.200313422823410.1016/S0924‑977X(03)00009‑912888181
     [Google Scholar]
  49. MurphyS.E. de CatesA.N. GillespieA.L. GodlewskaB.R. ScaifeJ.C. WrightL.C. CowenP.J. HarmerC.J. Translating the promise of 5HT 4 receptor agonists for the treatment of depression.Psychol. Med.20215171111112010.1017/S003329172000060432241310
     [Google Scholar]
  50. VidalR. Pilar-CuéllarF. dos AnjosS. LingeR. TreceñoB. VargasV.I. Rodriguez-GaztelumendiA. MostanyR. CastroE. DiazA. ValdizánE.M. PazosA. New strategies in the development of antidepressants: Towards the modulation of neuroplasticity pathways.Curr. Pharm. Des.201117552153310.2174/13816121179516408621375480
     [Google Scholar]
  51. RosséG. SchaffhauserH. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment.Curr. Top. Med. Chem.201010220722110.2174/15680261079041103620166958
     [Google Scholar]
  52. HealD.J. SmithS.L. FisasA. CodonyX. BuschmannH. Selective 5-HT6 receptor ligands: Progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders.Pharmacol. Ther.2008117220723110.1016/j.pharmthera.2007.08.00618068807
     [Google Scholar]
  53. MonsmaF.J.Jr ShenY. WardR.P. HamblinM.W. SibleyD.R. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs.Mol. Pharmacol.19934333203277680751
     [Google Scholar]
  54. WesołowskaA. NikiforukA. Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression.Neuropharmacology20075251274128310.1016/j.neuropharm.2007.01.00717320917
     [Google Scholar]
  55. HedlundP.B. The 5-HT7 receptor and disorders of the nervous system: An overview.Psychopharmacology2009206334535410.1007/s00213‑009‑1626‑019649616
     [Google Scholar]
  56. MullinsU. GianutsosG. EisonA.S. Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus.Neuropsychopharmacology199921335236710.1016/S0893‑133X(99)00041‑X10457532
     [Google Scholar]
  57. RothB.L. CraigoS.C. ChoudharyM.S. UluerA. MonsmaF.J.Jr ShenY. MeltzerH.Y. SibleyD.R. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.J. Pharmacol. Exp. Ther.19942683140314107908055
     [Google Scholar]
  58. BijataM. BączyńskaE. MüllerF.E. BijataK. MasternakJ. KrzystyniakA. SzewczykB. SiwiecM. AntoniukS. RoszkowskaM. FigielI. MagnowskaM. OlszyńskiK.H. WardakA.D. HogendorfA. RuszczyckiB. GorinskiN. LabusJ. StępieńT. TarkaS. BojarskiA.J. TokarskiK. FilipkowskiR.K. PonimaskinE. WlodarczykJ. Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior.Cell Rep.2022381111053210.1016/j.celrep.2022.11053235294881
     [Google Scholar]
  59. RathoreA. AsatiV. KashawS.K. AgarwalS. ParwaniD. BhattacharyaS. MallickC. The recent development of piperazine and piperidine derivatives as antipsychotic agents.Mini Rev. Med. Chem.202121336237910.2174/138955752066620091009232732912125
     [Google Scholar]
  60. SharmaA. WakodeS. FayazF. KhasimbiS. PottooF.H. KaurA. An overview of piperazine scaffold as promising nucleus for different therapeutic targets.Curr. Pharm. Des.202026354373438510.2174/138161282666620041715481032303168
     [Google Scholar]
  61. DurandC.S. Recent advances in the synthesis of piperazines: Focus on C–H functionalization.Organics20212433734710.3390/org2040018
     [Google Scholar]
  62. KumarR.R. SahuB. PathaniaS. SinghP.K. AkhtarM.J. KumarB. Piperazine, a key substructure for antidepressants: Its role in developments and structure‐activity relationships.ChemMedChem202116121878190110.1002/cmdc.20210004533751807
     [Google Scholar]
  63. ShaquiquzzamanM. VermaG. MarellaA. AkhterM. AkhtarW. KhanM.F. TasneemS. AlamM.M. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents.Eur. J. Med. Chem.201510248752910.1016/j.ejmech.2015.07.02626310894
     [Google Scholar]
  64. BritoA.F. MoreiraL.K.S. MenegattiR. CostaE.A. Piperazine derivatives with central pharmacological activity used as therapeutic tools.Fundam. Clin. Pharmacol.2019331132410.1111/fcp.1240830151922
     [Google Scholar]
  65. ChoudharyD. KumarB. KaurR. Nitrogen‐containing heterocyclic compounds: A ray of hope in depression?Chem. Biol. Drug Des.20241032e1447910.1111/cbdd.1447938361139
     [Google Scholar]
  66. ClarkeD.E. NarrowW.E. RegierD.A. KuramotoS.J. KupferD.J. KuhlE.A. GreinerL. KraemerH.C. DSM-5 field trials in the United States and Canada, Part I: Study design, sampling strategy, implementation, and analytic approaches.Am. J. Psychiatry20131701435810.1176/appi.ajp.2012.1207099823111546
     [Google Scholar]
  67. WagerT.D. WooC.W. Imaging biomarkers and biotypes for depression.Nat. Med.2017231161710.1038/nm.426428060802
     [Google Scholar]
  68. WaltherA. CannistraciC.V. SimonsK. DuránC. GerlM.J. WehrliS. KirschbaumC. Lipidomics in major depressive disorder.Front. Psychiatry2018945910.3389/fpsyt.2018.0045930374314
     [Google Scholar]
  69. WatkinsP.A. HamiltonJ.A. LeafA. SpectorA.A. MooreS.A. AndersonR.E. MoserH.W. NoetzelM.J. KatzR. Brain uptake and utilization of fatty acids: Applications to peroxisomal biogenesis diseases.J. Mol. Neurosci.2001162-3879210.1385/JMN:16:2‑3:8711478388
     [Google Scholar]
  70. HorrobinD.F. BennettC.N. Depression and bipolar disorder: Relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis Possible candidate genes.Prostaglandins Leukot. Essent. Fatty Acids199960421723410.1054/plef.1999.003710397403
     [Google Scholar]
  71. DemirkanA. IsaacsA. UgocsaiP. LiebischG. StruchalinM. RudanI. WilsonJ.F. PramstallerP.P. GyllenstenU. CampbellH. SchmitzG. OostraB.A. van DuijnC.M. Plasma phosphatidylcholine and sphingomyelin concentrations are associated with depression and anxiety symptoms in a Dutch family-based lipidomics study.J. Psychiatr. Res.201347335736210.1016/j.jpsychires.2012.11.00123207112
     [Google Scholar]
  72. ParianteC.M. Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation.Eur. Neuropsychopharmacol.201727655455910.1016/j.euroneuro.2017.04.00128479211
     [Google Scholar]
  73. MockingR.J.T. NaviauxJ.C. LiK. WangL. MonkJ.M. BrightA.T. FigueroaC.A. ScheneA.H. RuhéH.G. AssiesJ. NaviauxR.K. Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence.Transl. Psychiatry20211113710.1038/s41398‑020‑01182‑w33431800
     [Google Scholar]
  74. HuangT. BalasubramanianR. YaoY. ClishC.B. ShadyabA.H. LiuB. TworogerS.S. RexrodeK.M. MansonJ.E. KubzanskyL.D. HankinsonS.E. Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: A meta-analysis of individual data from three independent samples of US postmenopausal women.Mol. Psychiatry20212673315332710.1038/s41380‑020‑00870‑932859999
     [Google Scholar]
  75. PintoB. CondeT. DominguesI. DominguesM.R. Adaptation of lipid profiling in depression disease and treatment: A critical review.Int. J. Mol. Sci.20222342032
     [Google Scholar]
  76. ChanP. SuridjanI. MohammadD. HerrmannN. MazereeuwG. HillyerL.M. MaD.W.L. OhP.I. LanctotK.L. Novel phospholipid signature of depressive symptoms in patients with coronary artery disease.J. Am. Heart Assoc.201857e008278
     [Google Scholar]
  77. HennebelleM. OtokiY. YangJ. HammockB.D. LevittA.J. TahaA.Y. SwardfagerW. Altered soluble epoxide hydrolase-derived oxylipins in patients with seasonal major depression: An exploratory study.Psychiatry Res.20172529410110.1016/j.psychres.2017.02.05628259037
     [Google Scholar]
  78. HomoroganC. NituscaD. EnatescuV. SchubartP. MoraruC. SocaciuC. MarianC. Untargeted plasma metabolomic profiling in patients with major depressive disorder using ultra-high performance liquid chromatography coupled with mass spectrometry.Metabolites2021117466
     [Google Scholar]
  79. WangD. XiaoH. LvX. ChenH. WeiF. Crit. Rev. Anal. Chem.2023132
     [Google Scholar]
  80. WangQ. TimberlakeM.A.II PrallK. DwivediY. The recent progress in animal models of depression.Prog. Neuropsychopharmacol. Biol. Psychiatry2017779910910.1016/j.pnpbp.2017.04.00828396255
     [Google Scholar]
  81. WillnerP. Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation.Psychopharmacology1997134431932910.1007/s0021300504569452163
     [Google Scholar]
  82. Yankelevitch-YahavR. FrankoM. HulyA. DoronR. The forced swim test as a model of depressive-like behavior.J. Vis. Exp.20159752587
     [Google Scholar]
  83. O’NeilM.F. MooreN.A. Animal models of depression: Are there any?Hum. Psychopharmacol.200318423925410.1002/hup.49612766928
     [Google Scholar]
  84. TelnerJ.I. SinghalR.L. Psychiatric progress.J. Psychiatr. Res.198418320721510.1016/0022‑3956(84)90011‑66492008
     [Google Scholar]
  85. CryanJ.F. MombereauC. VassoutA. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice.Neurosci. Biobehav. Rev.2005294-557162510.1016/j.neubiorev.2005.03.00915890404
     [Google Scholar]
  86. StahlS.M. Lee-ZimmermanC. CartwrightS. MorrissetteD.A. Serotonergic drugs for depression and beyond.Curr. Drug Targets201314557858510.2174/138945011131405000723531115
     [Google Scholar]
  87. ArtigasF. Serotonin receptors involved in antidepressant effects.Pharmacol. Ther.2013137111913110.1016/j.pharmthera.2012.09.00623022360
     [Google Scholar]
  88. KimJ.Y. KimD. KangS.Y. ParkW.K. KimH.J. JungM.E. SonE.J. PaeA.N. KimJ. LeeJ. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant.Bioorg. Med. Chem. Lett.201020226439644210.1016/j.bmcl.2010.09.08120933409
     [Google Scholar]
  89. KangS.Y. ParkE.J. ParkW.K. KimH.J. JeongD. JungM.E. SongK.S. LeeS.H. SeoH.J. KimM.J. LeeM. HanH.K. SonE.J. PaeA.N. KimJ. LeeJ. Arylpiperazine-containing pyrrole 3-carboxamide derivatives targeting serotonin 5-HT2A, 5-HT2C, and the serotonin transporter as a potential antidepressant.Bioorg. Med. Chem. Lett.20102051705171110.1016/j.bmcl.2010.01.09320149649
     [Google Scholar]
  90. GuZ.S. XiaoY. ZhangQ.W. LiJ.Q. Synthesis and antidepressant activity of a series of arylalkanol and aralkyl piperazine derivatives targeting SSRI/5-HT 1A/5-HT 7.Bioorg. Med. Chem. Lett.201727245420542310.1016/j.bmcl.2017.11.00729138029
     [Google Scholar]
  91. ŻelaszczykD. JakubczykM. PytkaK. RapaczA. WalczakM. JaniszewskaP. PańczykK. ŻmudzkiP. SłoczyńskaK. MaronaH. WaszkielewiczA.M. Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.Bioorg. Med. Chem. Lett.2019292112667910.1016/j.bmcl.2019.12667931537425
     [Google Scholar]
  92. GuZ.S. ZhouA. XiaoY. ZhangQ.W. LiJ.Q. Synthesis and antidepressant-like activity of novel aralkyl piperazine derivatives targeting SSRI/5-HT 1A/5-HT 7.Eur. J. Med. Chem.201814470171510.1016/j.ejmech.2017.12.06329291438
     [Google Scholar]
  93. DharA.K. MaheshR. JindalA. BhattS. Piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides: Novel 5-HT3 receptor antagonists with antidepressant-like activity.Arch. Pharm.20153481344510.1002/ardp.20140029325581677
     [Google Scholar]
  94. Bang-AndersenB. RuhlandT. JørgensenM. SmithG. FrederiksenK. JensenK.G. ZhongH. NielsenS.M. HoggS. MørkA. StensbølT.B. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): A novel multimodal compound for the treatment of major depressive disorder.J. Med. Chem.20115493206322110.1021/jm101459g21486038
     [Google Scholar]
  95. MørkA. PehrsonA. BrennumL.T. NielsenS.M. ZhongH. LassenA.B. MillerS. WestrichL. BoyleN.J. SánchezC. FischerC.W. LiebenbergN. WegenerG. BundgaardC. HoggS. Bang-AndersenB. StensbølT.B. Pharmacological effects of Lu AA21004: A novel multimodal compound for the treatment of major depressive disorder.J. Pharmacol. Exp. Ther.2012340366667510.1124/jpet.111.18906822171087
     [Google Scholar]
  96. KubackaM. MogilskiS. BednarskiM. NowińskiL. DudekM. ŻmudzkaE. SiwekA. WaszkielewiczA.M. MaronaH. SatałaG. BojarskiA. FilipekB. PytkaK. Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action.Pharmacol. Biochem. Behav.2016141284110.1016/j.pbb.2015.11.01326647362
     [Google Scholar]
  97. WaszkielewiczA.M. PytkaK. RapaczA. WełnaE. JarzynaM. SatałaG. BojarskiA. SapaJ. ŻmudzkiP. FilipekB. MaronaH. Synthesis and evaluation of antidepressant-like activity of some 4-substituted 1-(2-methoxyphenyl)piperazine derivatives.Chem. Biol. Drug Des.201585332633510.1111/cbdd.1239425048712
     [Google Scholar]
  98. CanN.O. CanO.D. OsmaniyeD. Demir OzkayU. Synthesis of some novel thiadiazole derivative compounds and screening their antidepressant-like activities.Molecules2018234716
     [Google Scholar]
  99. PartykaA. Chłoń-RzepaG. WasikA. Jastrzębska-WięsekM. BuckiA. KołaczkowskiM. SatałaG. BojarskiA.J. WesołowskaA. Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT1A receptor functional profile.Bioorg. Med. Chem.201523121222110.1016/j.bmc.2014.11.00825435254
     [Google Scholar]
  100. WróbelM.Z. ChodkowskiA. MarciniakM. DawidowskiM. MaksymiukA. SiwekA. NowakG. TurłoJ. Synthesis of new 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and evaluation for their 5-HT1A and D2 receptor affinity and serotonin transporter inhibition.Bioorg. Chem.20209710366210.1016/j.bioorg.2020.10366232086055
     [Google Scholar]
  101. WilckenR. ZimmermannM.O. LangeA. ZahnS. BoecklerF.M. Using halogen bonds to address the protein backbone: A systematic evaluation.J. Comput. Aided Mol. Des.201226893594510.1007/s10822‑012‑9592‑822865255
     [Google Scholar]
  102. ModicaM.N. IntagliataS. PittalàV. SalernoL. SiracusaM.A. CagnottoA. SalmonaM. RomeoG. Synthesis and binding properties of new long-chain 4-substituted piperazine derivatives as 5-HT1A and 5-HT7 receptor ligands.Bioorg. Med. Chem. Lett.20152571427143010.1016/j.bmcl.2015.02.04225759032
     [Google Scholar]
  103. KędzierskaE. FiorinoF. MagliE. PoleszakE. WlaźP. Orzelska-GórkaJ. KnapB. KotlińskaJ.H. New arylpiperazine derivatives with antidepressant-like activity containing isonicotinic and picolinic nuclei: Evidence for serotonergic system involvement.Naunyn Schmiedebergs Arch. Pharmacol.2019392674375410.1007/s00210‑019‑01620‑730783717
     [Google Scholar]
  104. FiorinoF. MagliE. KędzierskaE. CianoA. CorvinoA. SeverinoB. PerissuttiE. FrecenteseF. Di VaioP. SacconeI. IzzoA.A. CapassoR. MassarelliP. RossiI. Orzelska-GòrkaJ. KotlińskaJ.H. SantagadaV. CaliendoG. New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation.Bioorg. Med. Chem.201725205820583710.1016/j.bmc.2017.09.01828943244
     [Google Scholar]
  105. FiorinoF. CianoA. MagliE. SeverinoB. CorvinoA. PerissuttiE. FrecenteseF. Di VaioP. IzzoA.A. CapassoR. MassarelliP. NenciniC. RossiI. KędzierskaE. Orzelska-GòrkaJ. BielenicaA. SantagadaV. CaliendoG. Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus.Eur. J. Med. Chem.201611013315010.1016/j.ejmech.2016.01.02126820556
     [Google Scholar]
  106. MagliE. KędzierskaE. KaczorA.A. SeverinoB. CorvinoA. PerissuttiE. FrecenteseF. SacconeI. MassarelliP. Gibuła-TarłowskaE. KotlińskaJ.H. SantagadaV. CaliendoG. FiorinoF. Synthesis, docking studies, and pharmacological evaluation of 5HT 2C ligands containing the N ′‐cyanoisonicotinamidine or N ′‐cyanopicolinamidine nucleus.Arch. Pharm.20193525180037310.1002/ardp.20180037331025433
     [Google Scholar]
  107. CzopekA. BuckiA. KołaczkowskiM. ZagórskaA. DropM. PawłowskiM. SiwekA. Głuch-LutwinM. PękalaE. ChrzanowskaA. StrugaM. PartykaA. WesołowskaA. Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability.Bioorg. Med. Chem.201927184163417310.1016/j.bmc.2019.07.04631383628
     [Google Scholar]
  108. ZhouH. LiM. LiuH. LiuZ. WangX. WangS. Design, synthesis, and biological evaluation of piperazine derivatives involved in the 5-HT 1A R/BDNF/PKA pathway.J. Enzyme Inhib. Med. Chem.2024391228618310.1080/14756366.2023.228618338078358
     [Google Scholar]
/content/journals/mrmc/10.2174/0113895575319878240612070850
Loading
Pharmaceutical Studies on Piperazine-based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters
Mini Rev Med Chem 25, 58 (2025); https://doi.org/10.2174/0113895575319878240612070850
/content/journals/mrmc/10.2174/0113895575319878240612070850
/content/journals/mrmc/10.2174/0113895575319878240612070850
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): 5-HT; antidepressant; Depression; detrimental impact; drug design; lipidomics; omics; piperazine; SSRIs

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test