{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:29:17Z","timestamp":1792070957422,"version":"4.4.0"},"reference-count":140,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,10]],"date-time":"2018-10-10T00:00:00Z","timestamp":1539129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2017\/27\/B\/NZ7\/01767"],"award-info":[{"award-number":["2017\/27\/B\/NZ7\/01767"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs have been performing far behind expectations during the last ten years. In this scenario, multi-target drugs are a promising approach against polygenic diseases with complex pathomechanisms such as schizophrenia. Indeed, second generation or atypical antipsychotics target a number of aminergic G protein-coupled receptors (GPCRs) simultaneously. Novel strategies in drug design and discovery against schizophrenia focus on targets beyond the dopaminergic hypothesis of the disease and even beyond the monoamine GPCRs. In particular these approaches concern proteins involved in glutamatergic and cholinergic neurotransmission, challenging the concept of antipsychotic activity without dopamine D2 receptor involvement. Potentially interesting compounds include ligands interacting with glycine modulatory binding pocket on N-methyl-d-aspartate (NMDA) receptors, positive allosteric modulators of \u03b1-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, positive allosteric modulators of metabotropic glutamatergic receptors, agonists and positive allosteric modulators of \u03b17 nicotinic receptors, as well as muscarinic receptor agonists. In this review we discuss classical and novel drug targets for schizophrenia, cover benefits and limitations of current strategies to design multi-target drugs and show examples of multi-target ligands as antipsychotics, including marketed drugs, substances in clinical trials, and other investigational compounds.<\/jats:p>","DOI":"10.3390\/ijms19103105","type":"journal-article","created":{"date-parts":[[2018,10,10]],"date-time":"2018-10-10T11:53:13Z","timestamp":1539172393000},"page":"3105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Multi-Target Approach for Drug Discovery against Schizophrenia"],"prefix":"10.3390","volume":"19","author":[{"given":"Magda","family":"Kondej","sequence":"first","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chod\u017aki St., Lublin PL-20093, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"St\u0119pnicki","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chod\u017aki St., Lublin PL-20093, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka A.","family":"Kaczor","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chod\u017aki St., Lublin PL-20093, Poland"},{"name":"School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, Kuopio FI-70211, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"St\u0119pnicki, P., Kondej, M., and Kaczor, A.A. (2018). Current Concepts and Treatments of Schizophrenia. Molecules, 23.","DOI":"10.3390\/molecules23082087"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1515\/revneuro-2013-0011","article-title":"Does the dopamine hypothesis explain schizophrenia?","volume":"24","author":"Lau","year":"2013","journal-title":"Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/nyas.12547","article-title":"The glutamate hypothesis of schizophrenia: Evidence from human brain tissue studies","volume":"1338","author":"Hu","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.drudis.2015.12.007","article-title":"In silico methods to address polypharmacology: Current status, applications and future perspectives","volume":"21","author":"Lavecchia","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1517\/17460441.2.6.799","article-title":"How to design multi-target drugs","volume":"2","author":"Szalay","year":"2007","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3389\/fnins.2016.00265","article-title":"Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies","volume":"10","author":"Nikolic","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neuroscience.2015.06.028","article-title":"The neuropathology of schizophrenia: A selective review of past studies and emerging themes in brain structure and cytoarchitecture","volume":"303","author":"Bakhshi","year":"2015","journal-title":"Neuroscience"},{"key":"ref_9","unstructured":"Rang, H.P., Ritter, J.M., Flower, R.J., and Henderson, G. (2016). Rang and Dale\u2019s Pharmacology, Elsevier. [8th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/sj.mp.4001556","article-title":"Treatments for schizophrenia: A critical review of pharmacology and mechanisms of action of antipsychotic drugs","volume":"10","author":"Miyamoto","year":"2005","journal-title":"Mol. Psychiatry"},{"key":"ref_11","first-page":"1163","article-title":"Clinical pharmacology of atypical antipsychotics: An update","volume":"13","author":"Mauri","year":"2014","journal-title":"EXCLI J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1080\/14740338.2016.1201475","article-title":"An update of safety of clinically used atypical antipsychotics","volume":"15","author":"Orsolini","year":"2016","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0031-6997(25)06671-2","article-title":"Effects of antipsychotic drugs on serotonin receptors","volume":"43","author":"Meltzer","year":"1991","journal-title":"Pharmacol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S0022-3565(25)38366-7","article-title":"Characterization of the 5-HT2 receptor antagonist MDL 100907 as a putative atypical antipsychotic: Behavioral, electrophysiological and neurochemical studies","volume":"266","author":"Sorensen","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_15","first-page":"373","article-title":"Treatment of neuroleptic induced akathisia with the 5-HT2 antagonist ritanserin","volume":"26","author":"Miller","year":"1990","journal-title":"Psychopharmacol. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1016\/0024-3205(95)00210-W","article-title":"The role of 5-HT2A receptors in antipsychotic activity","volume":"56","author":"Schmidt","year":"1995","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.pnpbp.2003.09.010","article-title":"Serotonin receptors: Their key role in drugs to treat schizophrenia","volume":"27","author":"Meltzer","year":"2003","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S0022-3565(24)38982-7","article-title":"Improving the treatment of schizophrenia: Focus on serotonin 5-HT1A receptors","volume":"295","author":"Millan","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.biopsych.2009.03.012","article-title":"The serotonin-1A receptor in anxiety disorders","volume":"66","author":"Akimova","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.bbr.2008.02.023","article-title":"The role of 5-HT1A receptors in learning and memory","volume":"195","author":"Ogren","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0014-2999(02)02430-5","article-title":"5-HT1A receptor activation and anti-cataleptic effects: High-efficacy agonists maximally inhibit haloperidol-induced catalepsy","volume":"453","author":"Prinssen","year":"2002","journal-title":"Eur. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00213-002-1121-3","article-title":"Postsynaptic 5-HT1A receptors mediate an increase in locomotor activity in the monoamine-depleted rat","volume":"163","author":"Mignon","year":"2002","journal-title":"Psychopharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1124\/jpet.105.092262","article-title":"5-Hydroxytryptamine 1A receptor blockade facilitates aversive learning in mice: Interactions with cholinergic and glutamatergic mechanisms","volume":"316","author":"Madjid","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1755-5949.2010.00211.x","article-title":"Therapeutic role of 5-HT1A receptors in the treatment of schizophrenia and Parkinson\u2019s disease","volume":"17","author":"Ohno","year":"2011","journal-title":"CNS Neurosci. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1476-5381.1988.tb11508.x","article-title":"Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors","volume":"94","author":"Kennett","year":"1988","journal-title":"Br. J. Pharmacol."},{"key":"ref_26","first-page":"75","article-title":"Hypersensitivity to meta-chlorophenylpiperazine (mCPP) in migraine and drug withdrawal","volume":"17","author":"Kalkman","year":"1997","journal-title":"Int. J. Clin. Pharmacol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1001\/archpsyc.1993.01820200034004","article-title":"m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia","volume":"50","author":"Krystal","year":"1993","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/ddr.1208","article-title":"5-HT2C receptor antagonists: Potential in schizophrenia","volume":"54","author":"Wood","year":"2001","journal-title":"Drug Dev. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.neuron.2017.03.016","article-title":"Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders","volume":"94","author":"Foster","year":"2017","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E8178","DOI":"10.1073\/pnas.1614347113","article-title":"Distinct cortical and striatal actions of a \u03b2-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties","volume":"113","author":"Urs","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4606","DOI":"10.2174\/092986711797379285","article-title":"Oligomerization of G protein-coupled receptors: Biochemical and biophysical methods","volume":"18","author":"Kaczor","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4588","DOI":"10.2174\/092986711797379320","article-title":"Oligomerization of G protein-coupled receptors: Computational methods","volume":"18","author":"Selent","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00894-016-3065-2","article-title":"The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: Homology modeling, docking and molecular dynamics","volume":"22","author":"Kaczor","year":"2016","journal-title":"J. Mol. Model."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"ra5","DOI":"10.1126\/scisignal.aab0467","article-title":"Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia","volume":"9","author":"Moreno","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.pharmthera.2010.02.001","article-title":"The effectiveness of multi-target agents in schizophrenia and mood disorders: Relevance of receptor signature to clinical action","volume":"126","author":"Wong","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fpsyt.2017.00042","article-title":"The Role of Norepinephrine and Its \u03b1-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A. Systematic Review","volume":"8","author":"Maletic","year":"2017","journal-title":"Front. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.pnpbp.2003.09.009","article-title":"\u03b1-Adrenoceptor modulation hypothesis of antipsychotic atypicality","volume":"27","author":"Svensson","year":"2003","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00213-014-3459-8","article-title":"\u03b12-Adrenoceptors are targets for antipsychotic drugs","volume":"231","author":"Brosda","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1017\/S1461145709990794","article-title":"Adjunctive \u03b12-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission","volume":"13","author":"Marcus","year":"2010","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s40263-013-0062-1","article-title":"The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain","volume":"27","author":"He","year":"2013","journal-title":"CNS Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.2174\/1381612821666150605105325","article-title":"Do Histamine receptor 3 antagonists have a place in the therapy for schizophrenia?","volume":"21","author":"Ellenbroek","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.bbr.2016.06.051","article-title":"Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases","volume":"312","author":"Sadek","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/npp.2015.189","article-title":"Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model","volume":"41","author":"Ghoshal","year":"2016","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"253","DOI":"10.2174\/1566524015666150330144821","article-title":"Possible involvement of muscarinic receptors in psychiatric disorders: A focus on schizophrenia and mood disorders","volume":"15","author":"Dean","year":"2015","journal-title":"Curr. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.biopsych.2005.04.007","article-title":"Reduced density of cholinergic interneurons in the ventral striatum in schizophrenia: An in situ hybridization study","volume":"58","author":"Holt","year":"2005","journal-title":"Biol. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1176\/appi.ajp.160.1.118","article-title":"In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia","volume":"160","author":"Raedler","year":"2003","journal-title":"Am. J. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/sj.mp.4001924","article-title":"Towards a muscarinic hypothesis of schizophrenia","volume":"12","author":"Raedler","year":"2007","journal-title":"Mol. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1017\/S0033291713002705","article-title":"Tobacco smoking in schizophrenia: Investigating the role of incentive salience","volume":"44","author":"Freeman","year":"2014","journal-title":"Psychol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.schres.2016.01.020","article-title":"nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives","volume":"171","author":"Parikh","year":"2016","journal-title":"Schizophr. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.2741\/2424","article-title":"Evidence for a role of nicotinic acetylcholine receptors in schizophrenia","volume":"12","author":"Adams","year":"2007","journal-title":"Front. Biosci. J. Virtual Libr."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Li, Y., Sun, L., Yang, T., Jiao, W., Tang, J., Huang, X., Huang, Z., Meng, Y., Luo, L., and Wang, X. (2018). Design and Synthesis of Novel Positive Allosteric Modulators of \u03b17 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice. J. Med. Chem.","DOI":"10.1021\/acs.jmedchem.7b01492"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41386-018-0066-0","article-title":"\u03b17 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia","volume":"43","author":"Neves","year":"2018","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/npp.2011.181","article-title":"From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment","volume":"37","author":"Moghaddam","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Yang, A.C., and Tsai, S.-J. (2017). New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081689"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1176\/appi.ajp.158.9.1367","article-title":"The emerging role of glutamate in the pathophysiology and treatment of schizophrenia","volume":"158","author":"Goff","year":"2001","journal-title":"Am. J. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/sj.mp.4001558","article-title":"Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence","volume":"10","author":"Harrison","year":"2005","journal-title":"Mol. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S0959-4388(00)00215-4","article-title":"NMDA receptor subunits: Diversity, development and disease","volume":"11","author":"Brickley","year":"2001","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.coph.2006.08.011","article-title":"NMDA receptor subunits: Function and pharmacology","volume":"7","author":"Paoletti","year":"2007","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_59","first-page":"63","article-title":"Potential role of amino acids in pathogenesis of schizophrenia","volume":"11","author":"Saleem","year":"2017","journal-title":"Int. J. Health Sci. (Quassim)"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1196\/annals.1300.008","article-title":"The NMDA receptor hypofunction model of psychosis","volume":"1003","author":"Farber","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lidow, M.S. (2000). Glutamate receptors in schizophrenia and antipsychotic drugs, in Neurotransmitter Receptors. Actions of Antipsychotic Medications, CRC Press.","DOI":"10.1201\/9781420041774"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/S0165-0173(99)00044-2","article-title":"Glutamate receptor expression in schizophrenic brain","volume":"31","author":"Healy","year":"2000","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1176\/appi.ajp.157.7.1141","article-title":"Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: Effects of schizophrenia","volume":"157","author":"Gao","year":"2000","journal-title":"Am. J. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1176\/appi.ajp.157.11.1811","article-title":"Ionotropic glutamate receptor binding and subunit mRNA expression in thalamic nuclei in schizophrenia","volume":"157","author":"Ibrahim","year":"2000","journal-title":"Am. J. Psychiatry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1001\/archpsyc.56.12.1117","article-title":"Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia","volume":"56","author":"Heckers","year":"1999","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.neuint.2006.09.006","article-title":"How do glial\u2013neuronal interactions fit into current neurotransmitter hypotheses of schizophrenia?","volume":"50","author":"Kondziella","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1177\/0269881106073126","article-title":"Glutamate and dopamine dysregulation in schizophrenia\u2014A synthesis and selective review","volume":"21","author":"Stone","year":"2007","journal-title":"J. Psychopharmacol. Oxf. Engl."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.neurobiolaging.2004.07.001","article-title":"Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T","volume":"26","author":"Kaiser","year":"2005","journal-title":"Neurobiol. Aging"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1523\/JNEUROSCI.20-11-04011.2000","article-title":"Intracellular modulation of NMDA receptor function by antipsychotic drugs","volume":"20","author":"Leveque","year":"2000","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/S0022-3565(24)37013-2","article-title":"Clozapine and haloperidol modulate N-methyl-d-aspartate- and non-N-methyl-d-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro","volume":"283","author":"Arvanov","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00406-013-0399-y","article-title":"Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders","volume":"263","author":"Hashimoto","year":"2013","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"26","DOI":"10.2174\/1568026611313010005","article-title":"Allosteric modulators for the treatment of schizophrenia: Targeting glutamatergic networks","volume":"13","author":"Menniti","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"473","DOI":"10.4155\/fmc.15.4","article-title":"AMPA receptor-positive allosteric modulators for the treatment of schizophrenia: An overview of recent patent applications","volume":"7","author":"Ward","year":"2015","journal-title":"Future Med. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Herman, E.J., Bubser, M., Conn, P.J., and Jones, C.K. (2012). Metabotropic glutamate receptors for new treatments in schizophrenia. Handb. Exp. Pharmacol., 297\u2013365.","DOI":"10.1007\/978-3-642-25758-2_11"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.pnpbp.2015.02.012","article-title":"Perspectives on the mGluR2\/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end?","volume":"60","author":"Li","year":"2015","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40263-014-0213-z","article-title":"Glycogen synthase kinase-3 as a therapeutic target for cognitive dysfunction in neuropsychiatric disorders","volume":"29","author":"Nolan","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/978-3-319-58811-7_14","article-title":"PDE Inhibitors for the Treatment of Schizophrenia","volume":"17","author":"Snyder","year":"2017","journal-title":"Adv. Neurobiol."},{"key":"ref_78","first-page":"CD007967","article-title":"Acetylcholinesterase inhibitors for schizophrenia","volume":"1","author":"Singh","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.drudis.2013.01.008","article-title":"Shifting from the single to the multitarget paradigm in drug discovery","volume":"18","author":"Giulianotti","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3390\/ph7020113","article-title":"From Single Target to Multitarget\/Network Therapeutics in Alzheimer\u2019s Therapy","volume":"7","author":"Zheng","year":"2014","journal-title":"Pharmaceuticals"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ejmech.2014.01.060","article-title":"Multifunctional compounds: Smart molecules for multifactorial diseases","volume":"76","author":"Bansal","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_82","first-page":"168","article-title":"Review. One Drug for Multiple Targets: A Computational Perspective","volume":"60","author":"Naveja","year":"2016","journal-title":"J. Mex. Chem. Soc."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Talevi, A. (2015). Multi-target pharmacology: Possibilities and limitations of the \u201cskeleton key approach\u201d from a medicinal chemist perspective. Front. Pharmacol., 6.","DOI":"10.3389\/fphar.2015.00205"},{"key":"ref_84","first-page":"1423","article-title":"Multifunctional ligands\u2014A new approach in the search for drugs against multi-factorial diseases","volume":"69","author":"Wichur","year":"2015","journal-title":"Postepy Hig. Med. Doswiadczalnej Online"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.1021\/jm058225d","article-title":"Designed Multiple Ligands. An Emerging Drug Discovery Paradigm","volume":"48","author":"Morphy","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/cmdc.201500599","article-title":"Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics","volume":"11","author":"Kaczor","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1016\/j.drudis.2016.08.001","article-title":"Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders","volume":"21","author":"Bawa","year":"2016","journal-title":"Drug Discov. Today"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrd1346","article-title":"Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia","volume":"3","author":"Roth","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1185\/03007990152673864","article-title":"Focus on Clozapine","volume":"17","author":"Naheed","year":"2001","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"201","DOI":"10.9740\/mhc.2017.09.201","article-title":"Graphic representation of pharmacology: Development of an alternative model","volume":"7","author":"Saklad","year":"2018","journal-title":"Ment. Health Clin."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1017\/S1461145713000795","article-title":"Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats","volume":"17","author":"Boyda","year":"2014","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.psyneuen.2014.01.018","article-title":"Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats","volume":"42","author":"He","year":"2014","journal-title":"Psychoneuroendocrinology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/tpj.2009.18","article-title":"Olanzapine-induced weight gain is associated with the -759C\/T and -697G\/C polymorphisms of the HTR2C gene","volume":"9","author":"Godlewska","year":"2009","journal-title":"Pharmacogenomics J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1192\/S0007125000298115","article-title":"Psychopharmacology of olanzapine. A. review","volume":"38","author":"Stephenson","year":"1999","journal-title":"Br. J. Psychiatry Suppl."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/cmdc.200800074","article-title":"Multi-receptor binding profile of clozapine and olanzapine: A structural study based on the new \u03b22 adrenergic receptor template","volume":"3","author":"Selent","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"81","DOI":"10.12740\/PP\/32923","article-title":"Misuse and abuse of quetiapine","volume":"49","author":"Habrat","year":"2015","journal-title":"Psychiatr. Pol."},{"key":"ref_97","unstructured":"George, B., and Craig, S. (2017). Brenner and Stevens\u2019 Pharmacology, Elsevier. [5th ed.]."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3810\/pgm.2013.09.2706","article-title":"Weight considerations in psychotropic drug prescribing and switching","volume":"125","author":"Hasnain","year":"2013","journal-title":"Postgrad. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3084859","DOI":"10.1155\/2017\/3084859","article-title":"Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews","volume":"2017","author":"Fornaro","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.biopsych.2016.10.011","article-title":"New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy","volume":"81","author":"Urs","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bcp.2014.10.014","article-title":"New functional activity of aripiprazole revealed. Robust antagonism of D2 dopamine receptor stimulated by G\u03b2\u03b3 antagonism","volume":"93","author":"Brust","year":"2015","journal-title":"Biochem Pharmacol."},{"key":"ref_102","first-page":"411","article-title":"Partial dopamine agonists in the treatment of psychosis","volume":"109","author":"Tamminga","year":"2002","journal-title":"J. Neural Transm. Vienna Austria 1996"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"488","DOI":"10.2174\/138161210790361461","article-title":"Third generation antipsychotic drugs: Partial agonism or receptor functional selectivity?","volume":"16","author":"Mailman","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"251","DOI":"10.2165\/00023210-200418040-00005","article-title":"Dopamine partial agonists: A new class of antipsychotic","volume":"18","author":"Lieberman","year":"2004","journal-title":"CNS Drugs"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"18488","DOI":"10.1073\/pnas.1104807108","article-title":"Discovery of \u03b2-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy","volume":"108","author":"Allen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1124\/jpet.102.033175","article-title":"Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors","volume":"302","author":"Burris","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/sj.npp.1300203","article-title":"Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology","volume":"28","author":"Shapiro","year":"2003","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/S0893-133X(98)00099-2","article-title":"Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes","volume":"20","author":"Lawler","year":"1999","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1124\/jpet.109.160598","article-title":"In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2\/3 receptor agonists 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740) and (\u2212)-2-oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic acid (LY379268)","volume":"331","author":"Fell","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"13656","DOI":"10.1073\/pnas.0803522105","article-title":"Antagonism of dopamine D2 receptor\/\u03b2-arrestin 2 interaction is a common property of clinically effective antipsychotics","volume":"105","author":"Masri","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.neuropharm.2008.03.015","article-title":"Recruitment of \u03b2-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling","volume":"54","author":"Klewe","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Ribeiro, E.L.A., de Mendon\u00e7a Lima, T., Vieira, M.E.B., Storpirtis, S., and Aguiar, P.M. (2018). Efficacy and safety of aripiprazole for the treatment of schizophrenia: An overview of systematic reviews. Eur. J. Clin. Pharmacol.","DOI":"10.1007\/s00228-018-2498-1"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(13)60733-3","article-title":"Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis","volume":"382","author":"Leucht","year":"2013","journal-title":"Lancet Lond. Engl."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"207","DOI":"10.9740\/mhc.2017.09.207","article-title":"Brexpiprazole: A review of a new treatment option for schizophrenia and major depressive disorder","volume":"7","author":"Diefenderfer","year":"2017","journal-title":"Ment. Health Clin."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3371\/CSRP.MCCI.010316","article-title":"Brexpiprazole for the Treatment of Schizophrenia: A Review of this Novel Serotonin-Dopamine Activity Modulator","volume":"9","author":"McEvoy","year":"2016","journal-title":"Clin. Schizophr. Relat. Psychoses"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"221","DOI":"10.9740\/mhc.2017.09.221","article-title":"Review of cariprazine in management of psychiatric illness","volume":"7","author":"Campbell","year":"2017","journal-title":"Ment. Health Clin."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"5144","DOI":"10.2174\/1381612822666160701084447","article-title":"The Novel Antipsychotic Cariprazine (RGH-188): State-of-the-Art in the Treatment of Psychiatric Disorders","volume":"22","author":"Orsolini","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13065-018-0422-5","article-title":"Structural determinants influencing halogen bonding: A case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands","volume":"12","author":"Marciniec","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ejmech.2012.11.042","article-title":"Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A\/5-HT2A\/5-HT7 and dopamine D2\/D3 receptors","volume":"60","author":"Zajdel","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1021\/jm800689g","article-title":"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","volume":"52","author":"Butini","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4803","DOI":"10.1021\/jm100294b","article-title":"Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors","volume":"53","author":"Butini","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1016\/j.bmc.2011.12.039","article-title":"Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor\u20145-HT1A\/5-HT2A\/5-HT7 and D2\/D3\/D4\u2014Agents: The synthesis and pharmacological evaluation","volume":"20","author":"Zajdel","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"3638","DOI":"10.1016\/j.bmc.2017.04.046","article-title":"The impact of the halogen bonding on D2 and 5-HT1A\/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties","volume":"25","author":"Partyka","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ejmech.2013.12.043","article-title":"Design, synthesis, pharmacological evaluation and computational studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics","volume":"74","author":"Bhosale","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_125","first-page":"40","article-title":"SSRIs and depressive symptoms in schizophrenia: A. systematic review","volume":"59","author":"Dapper","year":"2017","journal-title":"Tijdschr. Voor Psychiatr."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0960-894X(02)00996-4","article-title":"SLV310, a novel, potential antipsychotic, combining potent dopamine D2 receptor antagonism with serotonin reuptake inhibition","volume":"13","author":"Smid","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"6855","DOI":"10.1021\/jm050148z","article-title":"Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[\u03c9-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition","volume":"48","author":"Smid","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1021\/jm401958n","article-title":"Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders","volume":"57","author":"Li","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.ejmech.2018.01.002","article-title":"Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects","volume":"145","author":"Zajdel","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4807","DOI":"10.1016\/S0968-0896(03)00487-5","article-title":"Design, synthesis and pharmacological profile of novel dopamine D2 receptor ligands","volume":"11","author":"Menegatti","year":"2003","journal-title":"Bioorg. Med. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.bbr.2012.09.016","article-title":"New insights into pharmacological profile of LASSBio-579, a multi-target N-phenylpiperazine derivative active on animal models of schizophrenia","volume":"237","author":"Neves","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ejmech.2013.05.027","article-title":"Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as homologues of the antipsychotic lead compound LASSBio-579","volume":"66","author":"Pompeu","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neuint.2016.03.003","article-title":"In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic","volume":"96","author":"Kaczor","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3233\/JAD-151146","article-title":"AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders","volume":"53","author":"Ivachtchenko","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neuropharm.2006.03.021","article-title":"QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine","volume":"51","author":"Brea","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"5299","DOI":"10.1016\/j.bmcl.2015.09.045","article-title":"Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics","volume":"25","author":"Huang","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4671","DOI":"10.1021\/jm400408r","article-title":"Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics","volume":"56","author":"Chen","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.ejmech.2016.07.038","article-title":"Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics","volume":"123","author":"Chen","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.1016\/j.bmc.2017.07.040","article-title":"Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics","volume":"25","author":"Xiamuxi","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1016\/j.bmcl.2016.04.087","article-title":"Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics","volume":"26","author":"Yang","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T19:21:22Z","timestamp":1775244082000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/10\/3105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,10]]},"references-count":140,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["ijms19103105"],"URL":"https:\/\/doi.org\/10.3390\/ijms19103105","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,10]]}}}