Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Recent Development of Piperazine and Piperidine Derivatives as Antipsychotic Agents

Author(s): Akash Rathore, Vivek Asati, Sushil Kumar Kashaw*, Shivangi Agarwal, Deepa Parwani, Sushanta Bhattacharya and Chaitali Mallick

Volume 21, Issue 3, 2021

Published on: 09 September, 2020

Page: [362 - 379] Pages: 18

DOI: 10.2174/1389557520666200910092327

Price: $65

Abstract

Schizophrenia is a chronic neuropsychiatric disorder that affects nearly 1% of the global population. There are various anti-psychotic drugs available for the treatment of schizophrenia, but they have certain side effects; therefore, there is a need to explore and develop novel potential lead compounds against schizophrenia. The currently available drugs e.g. typical and atypical antipsychotics act on different dopamine and serotonin receptors and as per literature reports, various piperidine and piperazine derivatives have shown promising activity against these receptors. When different heterocyclic groups are attached to basic piperidine and piperazine rings, the antipsychotic activity is greatly potentiated. In this direction, various antipsychotic drugs have been synthesized at the laboratory level, and few are under clinical trial studies, such as Lu AE58054, PF-04802540, ORG25935, DMXB-A, Bitopertin, and ABT-126. In the present review, we include the studies related to the effect of different substituents on piperidine/piperazine derivatives and their anti-psychotic activity. Various series of synthesized compounds by other researchers with piperidine/piperazine nucleus have been reviewed and diagrammatically represented in the form of SAR (structure-activity relationships), which will help the scientists for the development of potential lead compounds.

Keywords: Schizophrenia, piperidine, piperazine derivatives, dopamine and serotonin receptors, antipsychotic drugs, neuropsychiatric disorder.

« Previous Next »
Graphical Abstract

[1]
Ekerholm, M.; Firus Waltersson, S.; Fagerberg, T.; Söderman, E.; Terenius, L.; Agartz, I.; Jönsson, E.G.; Nyman, H. Neurocognitive function in long-term treated schizophrenia: A five-year follow-up study. Psychiatry Res., 2012, 200(2-3), 144-152.
[http://dx.doi.org/10.1016/j.psychres.2012.05.008] [PMID: 22657952]
[2]
Michino, M.; Beuming, T.; Donthamsetti, P.; Newman, A.H.; Javitch, J.A.; Shi, L. What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands? Pharmacol. Rev., 2015, 67(1), 198-213.
[http://dx.doi.org/10.1124/pr.114.009944] [PMID: 25527701]
[3]
Kapur, S.; Remington, G. Atypical antipsychotics: New directions and new challenges in the treatment of schizophrenia. Annu. Rev. Med., 2001, 52(1), 503-517.
[http://dx.doi.org/10.1146/annurev.med.52.1.503] [PMID: 11160792]
[4]
Liddle, P.F. Schizophrenic syndromes, cognitive performance and neurological dysfunction. Psychol. Med., 1987, 17(1), 49-57.
[http://dx.doi.org/10.1017/S0033291700012976] [PMID: 3575577]
[5]
McCutcheon, R.A.; Reis Marques, T.; Howes, O.D. Schizophrenia-An overview. JAMA Psychiatry, 2019, 2, 1-10.
[PMID: 31664453]
[6]
Peprah, K.; Zhu, X.Y.; Eyunni, S.V.; Setola, V.; Roth, B.L.; Ablordeppey, S.Y. Multi-receptor drug design: Haloperidol as a scaffold for the design and synthesis of atypical antipsychotic agents. Bioorg. Med. Chem., 2012, 20(3), 1291-1297.
[http://dx.doi.org/10.1016/j.bmc.2011.12.019] [PMID: 22245230]
[7]
Zajdel, P.; Kos, T.; Marciniec, K.; Satała, G.; Canale, V.; Kamiński, K.; Hołuj, M.; Lenda, T.; Koralewski, R.; Bednarski, M.; Nowiński, L.; Wójcikowski, J.; Daniel, W.A.; Nikiforuk, A.; Nalepa, I.; Chmielarz, P.; Kuśmierczyk, J.; Bojarski, A.J.; Popik, P. Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects. Eur. J. Med. Chem., 2018, 145, 790-804.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.002] [PMID: 29407591]
[8]
Ikemoto, S. Brain reward circuitry beyond the mesolimbic dopamine system: A neurobiological theory. Neurosci. Biobehav. Rev., 2010, 35(2), 129-150.
[http://dx.doi.org/10.1016/j.neubiorev.2010.02.001] [PMID: 20149820]
[9]
Buckley, P.F.; Miller, B.J.; Lehrer, D.S.; Castle, D.J. Psychiatric comorbidities and schizophrenia. Schizophr. Bull., 2009, 35(2), 383-402.
[http://dx.doi.org/10.1093/schbul/sbn135] [PMID: 19011234]
[10]
Bucki, A.; Marcinkowska, M.; Śniecikowska, J.; Więckowski, K.; Pawłowski, M.; Głuch-Lutwin, M.; Gryboś, A.; Siwek, A.; Pytka, K.; Jastrzębska-Więsek, M.; Partyka, A.; Wesołowska, A.; Mierzejewski, P.; Kołaczkowski, M. Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based multifunctional ligands with antipsychotic-Like, mood-modulating, and procognitive activity. J. Med. Chem., 2017, 60(17), 7483-7501.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00839] [PMID: 28763213]
[11]
Leucht, S.; Cipriani, A.; Spineli, L.; Mavridis, D.; Örey, D.; Richter, F.; Samara, M.; Barbui, C.; Engel, R.R.; Geddes, J.R.; Kissling, W.; Stapf, M.P.; Lässig, B.; Salanti, G.; Davis, J.M. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet, 2013, 382(9896), 951-962.
[http://dx.doi.org/10.1016/S0140-6736(13)60733-3] [PMID: 23810019]
[12]
Stahl, S.M. Beyond the dopamine hypothesis of schizophrenia to three neural networks of psychosis: Dopamine, serotonin, and glutamate. CNS Spectr., 2018, 23(3), 187-191.
[http://dx.doi.org/10.1017/S1092852918001013] [PMID: 29954475]
[13]
Huang, L.; Zhang, W.; Zhang, X.; Yin, L.; Chen, B.; Song, J. Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics. Bioorg. Med. Chem. Lett., 2015, 25(22), 5299-5305.
[http://dx.doi.org/10.1016/j.bmcl.2015.09.045] [PMID: 26483200]
[14]
Goldberg, T.E.; Goldman, R.S.; Burdick, K.E.; Malhotra, A.K.; Lencz, T.; Patel, R.C.; Woerner, M.G.; Schooler, N.R.; Kane, J.M.; Robinson, D.G. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: Is it a practice effect? Arch. Gen. Psychiatry, 2007, 64(10), 1115-1122.
[http://dx.doi.org/10.1001/archpsyc.64.10.1115] [PMID: 17909123]
[15]
Xu, M.; Wang, Y.; Yang, F.; Wu, C.; Wang, Z.; Ye, B.; Jiang, X.; Zhao, Q.; Li, J.; Liu, Y.; Zhang, J.; Tian, G.; He, Y.; Shen, J.; Jiang, H. Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect. Eur. J. Med. Chem., 2018, 145, 74-85.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.099] [PMID: 29324345]
[16]
Leucht, S.; Kissling, W.; Davis, J.M. Second-generation antipsychotics for schizophrenia: Can we resolve the conflict? Psychol. Med., 2009, 39(10), 1591-1602.
[http://dx.doi.org/10.1017/S0033291709005455] [PMID: 19335931]
[17]
Kumar, A.; Singh, H.; Mishra, A.; Mishra, A.K. aripiprazole: An fda approved bioactive compound to treat schizophrenia- a mini review. Curr. Drug Discov. Technol., 2020, 17(1), 23-29.
[http://dx.doi.org/10.2174/1570163815666181008151718] [PMID: 30306873]
[18]
Nagoshi, Y.; Tominaga, T.; Fukui, K. Effect of aripiprazole augmentation for treatment-resistant somatoform disorder: A case series. J. Clin. Psychopharmacol., 2014, 34(3), 397-398.
[http://dx.doi.org/10.1097/JCP.0000000000000063] [PMID: 24525655]
[19]
Pan, P.Y.; Fu, A.T.; Yeh, C.B. Aripiprazole/methylphenidate combination in children and adolescents with disruptive mood dysregulation disorder and attention-deficit/hyperactivity disorder: An open-label study. J. Child Adolesc. Psychopharmacol., 2018, 28(10), 682-689.
[http://dx.doi.org/10.1089/cap.2018.0068] [PMID: 30148656]
[20]
Modugula, H.; Kumar, A. Risk Analysis of Lurasidone in Patients with Schizophrenia and Bipolar Depression, CNS & Neurological Disorders-Drug Targets; Formerly Current Drug Targets-CNS & Neurological Disorders, 2020.
[21]
Butini, S.; Gemma, S.; Campiani, G.; Franceschini, S.; Trotta, F.; Borriello, M.; Ceres, N.; Ros, S.; Coccone, S.S.; Bernetti, M.; De Angelis, M.; Brindisi, M.; Nacci, V.; Fiorini, I.; Novellino, E.; Cagnotto, A.; Mennini, T.; Sandager-Nielsen, K.; Andreasen, J.T.; Scheel-Kruger, J.; Mikkelsen, J.D.; Fattorusso, C. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior. J. Med. Chem., 2009, 52(1), 151-169.
[http://dx.doi.org/10.1021/jm800689g] [PMID: 19072656]
[22]
Kimura, K.T.; Asada, H.; Inoue, A.; Kadji, F.M.N. Im, D.; Mori, C.; Arakawa, T.; Hirata, K.; Nomura, Y.; Nomura, N.; Aoki, J.; Iwata, S.; Shimamura, T. Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine. Nat. Struct. Mol. Biol., 2019, 26(2), 121-128.
[http://dx.doi.org/10.1038/s41594-018-0180-z] [PMID: 30723326]
[23]
Wang, S.; Che, T.; Levit, A.; Shoichet, B.K.; Wacker, D.; Roth, B.L. Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature, 2018, 555(7695), 269-273.
[http://dx.doi.org/10.1038/nature25758] [PMID: 29466326]
[24]
Cao, X.; Zhang, Y.; Chen, Y.; Qiu, Y.; Yu, M.; Xu, X.; Liu, X.; Liu, B.F.; Zhang, L.; Zhang, G. Synthesis and biological evaluation of fused tricyclic heterocycle piperazine (Piperidine) derivatives as potential multireceptor atypical antipsychotics. J. Med. Chem., 2018, 61, 22.
[25]
Brindisi, M.; Butini, S.; Franceschini, S.; Brogi, S.; Trotta, F.; Ros, S.; Cagnotto, A.; Salmona, M.; Casagni, A.; Andreassi, M.; Saponara, S.; Gorelli, B.; Weikop, P.; Mikkelsen, J.D.; Scheel-Kruger, J.; Sandager-Nielsen, K.; Novellino, E.; Campiani, G.; Gemma, S. Targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors for developing effective antipsychotics: Synthesis, biological characterization, and behavioral studies. J. Med. Chem., 2014, 57(22), 9578-9597.
[http://dx.doi.org/10.1021/jm501119j] [PMID: 25343529]
[26]
Chen, Y.; Wang, S.; Xu, X.; Liu, X.; Yu, M.; Zhao, S.; Liu, S.; Qiu, Y.; Zhang, T.; Liu, B.F.; Zhang, G. Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics. J. Med. Chem., 2013, 56(11), 4671-4690.
[http://dx.doi.org/10.1021/jm400408r] [PMID: 23675993]
[27]
Chen, Y.; Xu, X.; Liu, X.; Yu, M.; Liu, B.F. Zhang, G Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine)-1, 3, 4-oxadiazoles derivatives as atypical antipsychotics. PLoS One, 2012, 7, 4.
[28]
Xiamuxi, H.; Wang, Z.; Li, J.; Wang, Y.; Wu, C.; Yang, F.; Jiang, X.; Liu, Y.; Zhao, Q.; Chen, W.; Zhang, J.; Xie, Y.; Hu, T.; Xu, M.; Guo, S.; Akber Aisa, H.; He, Y.; Shen, J. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics. Bioorg. Med. Chem., 2017, 25(17), 4904-4916.
[http://dx.doi.org/10.1016/j.bmc.2017.07.040] [PMID: 28774576]
[29]
Xu, M.; Wang, Y.; Yang, F.; Wu, C.; Wang, Z.; Ye, B.; Jiang, X.; Zhao, Q.; Li, J.; Liu, Y.; Zhang, J.; Tian, G.; He, Y.; Shen, J.; Jiang, H. Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs. Bioorg. Med. Chem. Lett., 2018, 28(4), 606-611.
[http://dx.doi.org/10.1016/j.bmcl.2018.01.038] [PMID: 29395980]
[30]
Chen, Y.; Lan, Y.; Cao, X.; Xu, X.; Zhang, J.; Yu, M.; Liu, X.; Liu, B.F.; Zhang, G. Synthesis and evaluation of amide, sulfonamide, and urea–benzisoxazole derivatives as potential atypical antipsychotics. MedChemComm, 2015, 6(5), 831-838.
[http://dx.doi.org/10.1039/C4MD00578C]
[31]
Cartmell, J.; Monn, J.A.; Schoepp, D.D. The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J. Pharmacol. Exp. Ther., 1999, 291(1), 161-170.
[PMID: 10490900]
[32]
Menezes, M.M.; Santini, M.A.; Benvenga, M.J.; Marek, G.J.; Merchant, K.M.; Mikkelsen, J.D.; Svensson, K.A. The mGlu2/3 receptor agonists LY354740 and LY379268 differentially regulate restraint-stress-induced expression of c-Fos in rat cerebral cortex. Neurosci. J., 2013, 2013736439
[http://dx.doi.org/10.1155/2013/736439] [PMID: 26317098]
[33]
Siever, L.J.; Zaluda, L.C.; McClure, M.M. . Clinical testing of a D1 agonist for cognitive enhancement in the schizophrenia spectrum 14th International Congress on Schizophrenia Research 2013.
[34]
Pharmacologic and clinical testing of a D1 agonist for cognitive 183 enhancement in neuropsychiatric disorders http://clinicaltrials.gov/ct2/show/NCT01519557? term=DAR-
[35]
Brexpiprazole in patients with acute schizophrenia www.clinicaltrials.gov/ct2/show/NCT01810380?term=brexpiprazole
[36]
Fleischhacker, W.W.; Hobart, M.; Ouyang, J.; Forbes, A.; Pfister, S.; McQuade, R.D.; Carson, W.H.; Sanchez, R.; Nyilas, M.; Weiller, E. Efficacy and safety of brexpiprazole (OPC-34712) as maintenance treatment in adults with schizophrenia a randomized, double-blind, placebo-controlled study. Int. J. Neuropsychopharmacol., 2017, 20(1), 11-21.
[PMID: 27566723]
[37]
Notte, G.T. New chemical entities entering phase III trials in 2011. Annu. Rep. Med. Chem., 2012, 47, 477-498.
[http://dx.doi.org/10.1016/B978-0-12-396492-2.00030-8]
[38]
A 6-month, randomized, double-blind, parallel-group, risperidonecontrolled, fixed-dose study evaluating the safety and efficacy of zicronapinein patients with schizophrenia EU clinical trials register, www.clinicaltrialsregister.eu/ctr-search/
[39]
Efficiency study to investigate blonanserin in treatment of schizophrenia when compared with risperidone http://clinicaltrials.gov/ct2/show/NCT01516 424? term=blonanserin
[40]
Turk, Tarek.; Alkhatib, Mahmoud. Morfin, Natalia Hernandez Blonanserin versus risperidone for schizophrenia The.. Cochrane database of systematic reviews., 2017.
[41]
A multi-center, inpatient and ambulatory, Phase II, double-blind, randomized, placebo-controlled proof of concept study of CYR- 101 in patients with DSM-IV schizophrenia EU clinical trials register, www.clinicaltrialsregister.eu/ctr-search/search? query=cyr-101
[42]
Study of CYR-101 in patients with schizophrenia http://clinicaltrials.gov/ct2/show/NCT00861796? term=cyr-101andrank
[43]
Saoud, J.; Luthringer, R.; Werner, S.; Noel, N.; Georgi, E. MINERVA NEUROSCIENCES Inc, assignee Gastro-resistant controlled release oral dosage forms United States patent application US 16/015,151, 2019.
[44]
Hesselink, J.M. Keppel, Idalopirdine (LY483518, SGS518, Lu AE 58054) in Alzheimer’s disease: never change a winning team and do not build exclusively on surrogates. Lessons Learned from Drug Development Trials. J. Pharmacol. Clin. Res., 2016, 2, 2.
[45]
Ramirez, MJ; Lai, MK; Tordera, RM; Francis, PT Serotonergic therapies for cognitive symptoms in Alzheimer’s disease rationale and current status., 2014.
[46]
Meltzer Herbert, Y. Method for treating schizophrenia and related diseases U.S. Patent No 8,735,397. 27, 2014.
[47]
Multipledose safety study of PF-04802540 in subjects with schizophrenia http://clinicaltrials.gov/ct2/show/NCT00876304? term=PF-
[48]
Jankowska, A.; Satała, G.; Partyka, A.; Wesołowska, A.; Bojarski, A.J.; Pawłowski, M.; Chłoń-Rzepa, G. Discovery and development of non-dopaminergic agents for the treatment of schizophrenia an overview of the preclinical and early clinical studies. Curr. Med. Chem., 2019, 26(25), 4885-4913.
[http://dx.doi.org/10.2174/0929867326666190710172002] [PMID: 31291870]
[49]
de Bejczy, A.; Nations, K.R.; Szegedi, A.; Schoemaker, J.; Ruwe, F.; Söderpalm, B. Efficacy and safety of the glycine transporter-1 inhibitor org 25935 for the prevention of relapse in alcohol-dependent patients: A randomized, double-blind, placebo-controlled trial. Alcohol. Clin. Exp. Res., 2014, 38(9), 2427-2435.
[http://dx.doi.org/10.1111/acer.12501] [PMID: 25257291]
[50]
Adjuvant treatment with a glycine uptake inhibitor in subjects with chronic schizophrenia http://clinicaltrials.gov/ct2/show/NCT00725075?term=ORG25935
[51]
Eddins, D.; Hamill, T.G.; Puri, V.; Cannon, C.E.; Vivian, J.A.; Sanabria-Bohórquez, S.M.; Cook, J.J.; Morrow, J.A.; Thomson, F.; Uslaner, J.M. The relationship between glycine transporter 1 occupancy and the effects of the glycine transporter 1 inhibitor RG1678 or ORG25935 on object retrieval performance in scopolamine impaired rhesus monkey. Psychopharmacology (Berl.), 2014, 231(3), 511-519.
[http://dx.doi.org/10.1007/s00213-013-3260-0] [PMID: 24051602]
[52]
Tsai, Guochuan Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry, 2004, 55, 5.
[53]
Effect of sarcosine on symptomatology, quality of life, oxidative stress and glutamatergic parametersin schizophrenia(PULSAR) http://clinicaltrials.gov/ct2/show/NCT01503359 ? term=sarcosine
[54]
Sarcosine(N-methylglycine)monotherapy for schizophrenia http://clinicaltrials.gov/ct2/show/NCT00328276?term=sarcosine
[55]
Tregellas, J.R.; Olincy, A.; Johnson, L.; Tanabe, J.; Shatti, S.; Martin, L.; Singel, D.; Du, Y.; Soti, F.; Kem, W.; Freedman, R. Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia. Neuropsychopharmacology, 2010, 35, 4.
[56]
Trial of DMXB-A in schizophrenia http://clinicaltrials.gov/ct2/show/NCT00100165? Term =DMXB-Aand
[57]
Bugarski-Kirola, D.; Blaettler, T.; Arango, C.; Fleischhacker, W.W.; Garibaldi, G.; Wang, A.; Dixon, M.; Bressan, R.A.; Nasrallah, H.; Lawrie, S.; Napieralski, J.; Ochi-Lohmann, T.; Reid, C.; Marder, S.R. Bitopertin in negative symptoms of schizophrenia results from the phase III Flash Lyte and Day Lyte studies. Biol. Psychiatry, 2017, 82(1), 8-16.
[http://dx.doi.org/10.1016/j.biopsych.2016.11.014] [PMID: 28117049]
[58]
Garay, R.P.; Samalin, L.; Hameg, A.; Llorca, P.M. Investigational drugs for anxiety in patients with schizophrenia. Expert Opin. Investig. Drugs, 2015, 24(4), 507-517.
[http://dx.doi.org/10.1517/13543784.2014.987339] [PMID: 25423603]
[59]
A study of RO4917838 (Bitopertin) in patients with sub-optimally controlled symptoms ofschizophrenia (WN25305)http://clinicaltrials.gov/ct2/show/NCT01235559?term=bitopertin
[60]
Haig, G.M.; Wang, D.; Zhao, J.; Othman, A.A.; Bain, E.E. Efficacy and Safety of the α7-Nicotinic acetylcholine receptor agonist ABT-126 in the treatment of cognitive impairment associated with schizophrenia results from a phase 2b randomized controlled Study in Smokers. J. Clin. Psychiat, 2018, 79, 3.
[61]
A randomized, double-blind, placebo controlled, dose-ranging, parallel-group study of the safety and efficacy of ABT-126 in the treatment of cognitive deficits in schizophrenia (CDS) EU clinical trialsregister.www.clinicaltrialsregister.eu/ctr-search/trial/2012–000418–13/GB(Accessed 6 October 2013)
[62]
Haig, G.; Wang, D.; Othman, A. Zhao, J the α7 nicotinic agonist ABT-126 in the treatment of cognitive impairment associated with schizophrenia in nonsmokers results from a randomized controlled phase 2b study. Neuropsychopharmacology, 2016, 41, 12.
[63]
Yatham, L.N.; Mackala, S.; Basivireddy, J.; Ahn, S.; Walji, N.; Hu, C.; Lam, R.W.; Torres, I.J. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: A randomised, open-label, pilot study. Lancet Psychiat, 2017, 4(3), 208-217.
[http://dx.doi.org/10.1016/S2215-0366(17)30046-9] [PMID: 28185899]

Rights & Permissions Print Cite
Article Metrics
71
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy