Multi-targeted drug design strategies for the treatment of schizophrenia

References

• Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067.
   PubMed Web of Science ®Google Scholar
• Stępnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Molecules. 2018;23(8):2087.
   PubMed Web of Science ®Google Scholar
• Buckley PF, Miller BJ, Lehrer DS, et al. Psychiatric comorbidities and Schizophrenia. Schizophr Bull. 2009;35:383–402.
   PubMed Web of Science ®Google Scholar
• Howell S, Yarovova E, Khwanda A, et al. Cardiovascular effects of psychotic illnesses and antipsychotic therapy. Heart. 2019;105:1852–1859.
   PubMed Web of Science ®Google Scholar
• Seifert R, Schirmer B. A simple mechanistic terminology of psychoactive drugs: a proposal. Naunyn-Schmiedeberg’s Arch Pharmacol. 2020;393:1331–1339.
   Google Scholar
• [cited 2020 Jun 15]. Available from: https://www.guidetopharmacology.org/
   Google Scholar
• Antolin AA, Workman P, Mestres J, et al. Polypharmacology in precision oncology: current applications and future prospects. Curr Pharm Des. 2016;22:6935–6945.
   PubMed Web of Science ®Google Scholar
• Raevsky OA, Mukhametov A, Grigorev VY, et al. Applications of multi-target computer-aided methodologies in molecular design of CNS drugs. Curr Med Chem. 2018;25:5293–5314.
   PubMed Web of Science ®Google Scholar
• Talevi A. Tailored multi-target agents. Applications and design considerations. Curr Pharm Des. 2016;22:3164–3170.
   PubMed Web of Science ®Google Scholar
• Kondej M, Stępnicki P, Kaczor AA. Multi-target approach for drug discovery against schizophrenia. Int J Mol Sci. 2018;19:3105.
   PubMed Web of Science ®Google Scholar
• Schizophrenia: SA. Diverse approaches to a complex disease. Science. 2002;296:692–695.
   PubMed Web of Science ®Google Scholar
• Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21 st century. J Psychopharmacol. 2015;29:97–115.
   PubMed Web of Science ®Google Scholar
• Davis KL, Kahn RS, Ko G, et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–1486.
   PubMed Web of Science ®Google Scholar
• Lau C-I, Wang H-C, Hsu J-L, et al. Does the dopamine hypothesis explain schizophrenia? Rev Neurosci. 2013;24:389–400.
   PubMed Web of Science ®Google Scholar
• Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160:13–23.
   PubMed Web of Science ®Google Scholar
• Kesby JP, Eyles DW, McGrath JJ, et al. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry. 2018;8:1–12.
   PubMed Web of Science ®Google Scholar
• Loonen AJM, Ivanova SA. Evolution of circuits regulating pleasure and happiness with the habenula in control. CNS Spectr. 2019;24:233–238.
   PubMed Web of Science ®Google Scholar
• Loonen AJ, Ivanova SA. The evolutionary old forebrain as site of action to develop new psychotropic drugs. J Psychopharmacol. 2018;32:1277–1285.
   PubMed Web of Science ®Google Scholar
• Rubio MD, Drummond JB, Meador-Woodruff JH. Glutamate receptor abnormalities in schizophrenia: implications for innovative treatments. Biomol Ther. 2012;20:1–18.
   PubMed Web of Science ®Google Scholar
• Wang M, Wong AH, Liu F. Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res. 2012;1476:154–163.
   PubMed Web of Science ®Google Scholar
• Eggers AE. A serotonin hypothesis of schizophrenia. Med Hypotheses. 2013;80:791–794.
   PubMed Web of Science ®Google Scholar
• Sumiyoshi T, Kunugi H, Nakagome K. Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia. Front Neurosci. 2014;8:395.
   PubMed Web of Science ®Google Scholar
• Aghajanian G. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev. 2000;31:302–312.
   PubMed Web of Science ®Google Scholar
• Yang A, Tsai S-J. New targets for Schizophrenia treatment beyond the Dopamine hypothesis. Int J Mol Sci. 2017;18:1689.
   PubMed Web of Science ®Google Scholar
• Schmidt MJ, Mirnics K. Neurodevelopment, GABA system dysfunction, and Schizophrenia. Neuropsychopharmacology. 2015;40:190–206.
   PubMed Web of Science ®Google Scholar
• Wassef A, Baker J, Kochan LD. GABA and Schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol. 2003;23:601–640.
   PubMed Web of Science ®Google Scholar
• Felder CC, Porter AC, Skillman TL, et al. Elucidating the role of muscarinic receptors in psychosis. Life Sci. 2001;68:2605–2613.
   PubMed Web of Science ®Google Scholar
• Vidal PM, Pacheco R. The cross-talk between the dopaminergic and the immune system involved in Schizophrenia. Front Pharmacol. 2020;11:394.
   PubMed Web of Science ®Google Scholar
• Frost DO, Tamminga CA, Medoff DR, et al. Neuroplasticity and schizophrenia. Biol Psychiatry. 2004;56:540–543.
   PubMed Web of Science ®Google Scholar
• Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3:353–359.
   PubMed Web of Science ®Google Scholar
• Chokhawala K, Stevens L Antipsychotic medications [Internet]. StatPearls [Internet]. StatPearls Publishing; 2020 [cited 2020 Jun 10]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519503/
   Google Scholar
• Ritter J, Flower R, Henderson G. Rang & Dale’s pharmacology. 9th ed. Amsterdam (Netherlands): Elsevier; 2019.
   Google Scholar
• Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223.
   PubMed Web of Science ®Google Scholar
• Crilly J. The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry. 2007;18:39–60.
   PubMed Web of Science ®Google Scholar
• Solmi M, Murru A, Pacchiarotti I, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–777.
   PubMed Web of Science ®Google Scholar
• Divac N, Prostran M, Jakovcevski I, et al. Second-generation antipsychotics and extrapyramidal adverse effects. Biomed Res Int. 2014;2014:656370.
   PubMed Web of Science ®Google Scholar
• Limandri BJ. Clinical use of dopamine modulators as third-generation antipsychotic agents. J Psychosoc Nurs Ment Health Serv. 2019;57:7–11.
   Web of Science ®Google Scholar
• Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18:251–267.
   PubMed Web of Science ®Google Scholar
• Mailman RB, Murthy V. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? Curr Pharm Des. 2010;16:488–501.
   PubMed Web of Science ®Google Scholar
• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm (Vienna). 2002;109:411–420.
   PubMed Web of Science ®Google Scholar
• Frampton JE. Brexpiprazole: a review in schizophrenia. Drugs. 2019;79:189–200.
   PubMed Web of Science ®Google Scholar
• Salem H, Nagpal C, Pigott T, et al. Revisiting antipsychotic-induced akathisia: current issues and prospective challenges. Curr Neuropharmacol. 2017;15:789–798.
   PubMed Web of Science ®Google Scholar
• Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48:6523–6543.
   PubMed Web of Science ®Google Scholar
• Medina-Franco JL, Giulianotti MA, Welmaker GS, et al. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov Today. 2013;18:495–501.
   PubMed Web of Science ®Google Scholar
• Zheng H, Fridkin M, Youdim M. From single target to multitarget/network therapeutics in alzheimer’s therapy. Pharmaceuticals. 2014;7:113–135.
   Google Scholar
• Bansal Y, Silakari O. Multifunctional compounds: smart molecules for multifactorial diseases. Eur J Med Chem. 2014;76:31–42.
   PubMed Web of Science ®Google Scholar
• Ramsay RR, Popovic-Nikolic MR, Nikolic K, et al. A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med. 2018;7:3.
   PubMed Web of Science ®Google Scholar
• DrugBank. [cited 2020 Jun 15]. Available from: https://www.drugbank.ca
   Google Scholar
• Therapeutic target database. [cited 2020 Jun 15]. Available from: http://bidd.nus.edu.sg/group/ttd/ttd.asp
   Google Scholar
• Chen C, Wu M, Cen S, et al. MTLD, a database of multiple target ligands, the updated version. Molecules. 2017;22:1375.
   Web of Science ®Google Scholar
• Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4:682–690.
   PubMed Web of Science ®Google Scholar
• Selent J, Bauer-Mehren A, López L, et al. A novel multilevel statistical method for the study of the relationships between multireceptorial binding affinity profiles and in vivo endpoints. Mol Pharmacol. 2010;77:149–158.
   PubMed Web of Science ®Google Scholar
• Bottegoni G, Favia AD, Recanatini M, et al. The role of fragment-based and computational methods in polypharmacology. Drug Discov Today. 2012;17:23–34.
   PubMed Web of Science ®Google Scholar
• Zhou J, Jiang X, He S, et al. Rational design of multitarget-directed ligands: strategies and emerging paradigms. J Med Chem. 2019;62:8881–8914.
   PubMed Web of Science ®Google Scholar
• Méndez-Lucio O, Naveja JJ, Vite-Caritino H, et al. Review. One drug for multiple targets: a computational perspective. J Mex Chem Soc. 2016;60:168–181.
   Web of Science ®Google Scholar
• Talevi A. Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front Pharmacol. 2015;6:205.
   PubMed Web of Science ®Google Scholar
• Korcsmáros T, Szalay MS, Böde C, et al. How to design multi-target drugs. Expert Opin Drug Discov. 2007;2:799–808.
   PubMed Web of Science ®Google Scholar
• Wichur T, Malawska B. [Multifunctional ligands–a new approach in the search for drugs against multi-factorial diseases]. Postepy Hig Med Dosw (Online). 2015;69:1423–1434.
   PubMedGoogle Scholar
• Ma XH, Shi Z, Tan C, et al. In-silico approaches to multi-target drug discovery: computer aided multi-target drug design, multi-target virtual screening. Pharm Res. 2010;27:739–749.
   PubMed Web of Science ®Google Scholar
• Sheng Z, Sun Y, Yin Z, et al. Advances in computational approaches in identifying synergistic drug combinations. Brief Bioinf. 2018;19:1172–1182.
   PubMed Web of Science ®Google Scholar
• Chua HE, Bhowmick SS, Tucker-Kellogg L. Synergistic target combination prediction from curated signaling networks: machine learning meets systems biology and pharmacology. Methods. 2017;129:60–80.
   PubMed Web of Science ®Google Scholar
• Lavecchia A, Cerchia C. In silico methods to address polypharmacology: current status, applications and future perspectives. Drug Discov Today. 2016;21:288–298.
   PubMed Web of Science ®Google Scholar
• Nikolic K, Mavridis L, Djikic T, et al. Drug design for CNS diseases: polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies. Front Neurosci. 2016;10:265.
   PubMed Web of Science ®Google Scholar
• Kaczor AA, Silva AG, Loza MI, et al. Structure-based virtual screening for dopamine D2 receptor ligands as potential antipsychotics. Chem Med Chem. 2016;11:718–729.
   Web of Science ®Google Scholar
• Zhang W, Pei J, Lai L. Computational multitarget drug design. J Chem Inf Model. 2017;57:403–412.
   PubMed Web of Science ®Google Scholar
• Shang E, Yuan Y, Chen X, et al. De Novo design of multitarget ligands with an iterative fragment-growing strategy. J Chem Inf Model. 2014;54:1235–1241.
   PubMed Web of Science ®Google Scholar
• Hartenfeller M, Zettl H, Walter M, et al. DOGS: reaction-driven de novo design of bioactive compounds. PLoS Comput Biol. 2012;8:e1002380.
   PubMed Web of Science ®Google Scholar
• Vinkers HM, de Jonge MR, Daeyaert FFD, et al. Synopsis: synthesize and optimize system in silico. J Med Chem. 2003;46:2765–2773.
   PubMed Web of Science ®Google Scholar
• Zhou J, Wu JH. Binding-site match maker (BSMM): a computational method for the design of multi-target ligands. Molecules. 2020;25:1821.
   Web of Science ®Google Scholar
• Ortuso F, Bagetta D, Maruca A, et al. Chemotheca: a community-populated molecular database for multi-target ligands identification and compound-repurposing. Front Chem. 2018;6:130.
   PubMed Web of Science ®Google Scholar
• Li H, Pei F, Taylor DL, et al. QuartataWeb: integrated chemical–protein-pathway mapping for polypharmacology and chemogenomics. Bioinformatics. 2020;36:3935–3937.
   PubMed Web of Science ®Google Scholar
• Szklarczyk D, Santos A, von Mering C, et al. STITCH 5: augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 2016;44:D380–D384.
   PubMed Web of Science ®Google Scholar
• Zhang C, Li Q, Meng L, et al. Design of novel dopamine D2 and serotonin 5-HT2A receptors dual antagonists toward schizophrenia: an integrated study with QSAR, molecular docking, virtual screening and molecular dynamics simulations. J Biomol Struct Dyn. 2019;38:1–26.
   PubMed Web of Science ®Google Scholar
• Kaczor AA, Targowska-Duda KM, Budzyńska B, et al. 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. Neurochem Int. 2016;96:84–99.
   PubMed Web of Science ®Google Scholar
• Kaczor AA, Targowska-Duda KM, Silva AG, et al. N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a multi-target ligand of aminergic GPCRs, as a potential antipsychotic. Biomolecules. 2020;10:10.
   Web of Science ®Google Scholar
• Kondej M, Bartyzel A, Pitucha M, et al. Synthesis, structural and thermal studies of 3-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-ethoxy-1H-indole (D2AAK1_3) as Dopamine D2 receptor ligand. Molecules. 2018;23:2249.
   Web of Science ®Google Scholar
• Kondej M, Wróbel TM, Silva AG, et al. Synthesis, pharmacological and structural studies of 5-substituted-3-(1-arylmethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as multi-target ligands of aminergic GPCRs. Eur J Med Chem. 2019;180:673–689.
   PubMed Web of Science ®Google Scholar
• Moffat JG, Rudolph J, Bailey D. Phenotypic screening in cancer drug discovery - past, present and future. Nat Rev Drug Discov. 2014;13:588–602.
   PubMed Web of Science ®Google Scholar
• Koutsoukas A, Simms B, Kirchmair J, et al. From in silico target prediction to multi-target drug design: current databases, methods and applications. J Proteomics. 2011;74:2554–2574.
   PubMed Web of Science ®Google Scholar
• Cho YS, Kwon HJ. Identification and validation of bioactive small molecule target through phenotypic screening. Bioorg Med Chem. 2012;20:1922–1928.
   PubMed Web of Science ®Google Scholar
• Morphy JR. Chapter 10: thechallenges of multi-target lead optimization. In: Morphy JR, Harris CJ, editors. Designing multi-target drugs. Cambridge (UK): RSC Publishing; 2012. p. 141–154.
   Google Scholar
• Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse Chemical function from a few good reactions. Angew Chem Int Ed Engl. 2001;40:2004–2021.
   PubMed Web of Science ®Google Scholar
• Suzuki A. Cross-coupling reactions of organoboranes: an easy way to construct C-C Bonds (Nobel Lecture). Angew Chem. 2011;50:6722–6737.
   Google Scholar
• Bolognesi ML. Polypharmacology in a single drug: multitarget drugs. Curr Med Chem. 2013;20:1639–1645.
   PubMed Web of Science ®Google Scholar
• Schumacher JE, Makela EH, Griffin HR. Multiple antipsychotic medication prescribing patterns. Ann Pharmacother. 2003;37:951–955.
   PubMed Web of Science ®Google Scholar
• Bolognesi ML. Harnessing polypharmacology with medicinal chemistry. ACS Med Chem Lett. 2019;10:273–275.
   PubMed Web of Science ®Google Scholar
• Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51:347–372.
   PubMed Web of Science ®Google Scholar
• Anighoro A, Bajorath J, Rastelli G. Polypharmacology: challenges and opportunities in drug discovery. J Med Chem. 2014;57:7874–7887.
   PubMed Web of Science ®Google Scholar
• Malo M, Brive L, Luthman K, et al. Selective pharmacophore models of dopamine D(1) and D(2) full agonists based on extended pharmacophore features. ChemMedChem. 2010;5:232–246.
   PubMed Web of Science ®Google Scholar
• Del Bello F, Ambrosini D, Bonifazi A, et al. Multitarget 1,4-Dioxane compounds combining favorable D2-like and 5-HT1A receptor interactions with potential for the treatment of Parkinson’s disease or Schizophrenia. ACS Chem Neurosci. 2019;10:2222–2228.
   PubMed Web of Science ®Google Scholar
• Canale V, Kurczab R, Partyka A, et al. N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT(7) receptor selectivity versus multireceptor profile. Bioorg Med Chem. 2016;24:130–139.
   PubMed Web of Science ®Google Scholar
• Xu M, Wang Y, Yang F, et al. Synthesis and biological evaluation of a series of novel pyridinecarboxamides as potential multi-receptor antipsychotic drugs. Bioorg Med Chem Lett. 2018;28:606–611.
   PubMed Web of Science ®Google Scholar
• van Hes R, Smid P, Stroomer CNJ, et al. SLV310, a novel, potential antipsychotic, combining potent dopamine D2 receptor antagonism with serotonin reuptake inhibition. Bioorg Med Chem Lett. 2003;13:405–408.
   PubMed Web of Science ®Google Scholar
• Patil P, Schwartz TL. Fine tuning the use of second generation antipsychotics. J Ment Health Clin Psychol. 2018;2:22–39.
   Google Scholar
• Smid P, Coolen HKAC, Keizer HG, et al. Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition. J Med Chem. 2005;48:6855–6869.
   PubMed Web of Science ®Google Scholar
• Li P, Zhang Q, Robichaud AJ, et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J Med Chem. 2014;57:2670–2682.
   PubMed Web of Science ®Google Scholar
• Zajdel P, Marciniec K, Maślankiewicz A, et al. Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor - 5-HT 1A/5-HT 2A/5-HT 7 and D 2/D 3/D 4 - agents: the synthesis and pharmacological evaluation. Bioorg Med Chem. 2012;20:1545–1556.
   PubMed Web of Science ®Google Scholar
• Zajdel P, Marciniec K, Maślankiewicz A, et al. Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT 1A/5-HT2A/5-HT7 and dopamine D 2/D3 receptors. Eur J Med Chem. 2013;60:42–50.
   PubMed Web of Science ®Google Scholar
• Zajdel P, Kos T, Marciniec K, et al. 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.
   PubMed Web of Science ®Google Scholar
• Ivachtchenko AV, Lavrovsky Y, Okun I. AVN-101: a multi-target drug candidate for the treatment of CNS disorders. J Alzheimers Dis. 2016;53:583–620.
   PubMed Web of Science ®Google Scholar
• Brea J, Castro M, Loza MI, et al. QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine. Neuropharmacology. 2006;51:251–262.
   PubMed Web of Science ®Google Scholar
• Huang L, Zhang W, Zhang X, et al. Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics. Bioorg Med Chem Lett. 2015;25:5299–5305.
   PubMed Web of Science ®Google Scholar
• Xiamuxi H, Wang Z, Li J, et al. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics. Bioorg Med Chem. 2017;25:4904–4916.
   PubMed Web of Science ®Google Scholar
• Dedic N, Jones PG, Hopkins SC, et al. SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther. 2019;371:1–14.
   PubMed Web of Science ®Google Scholar
• Chen Y, Wang S, Xu X, et al. Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics. J Med Chem. 2013;56:4671–4690.
   PubMed Web of Science ®Google Scholar
• Czopek A, Bucki A, Kołaczkowski M, et al. Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: pharmacological evaluation and investigation of cytotoxicity and metabolic stability. Bioorg Med Chem. 2019;27:4163–4173.
   PubMed Web of Science ®Google Scholar
• Chen X-W, Sun -Y-Y, Fu L, et al. 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. Eur J Med Chem. 2016;123:332–353.
   PubMed Web of Science ®Google Scholar
• Cao X, Chen Y, Zhang Y, et al. Synthesis and biological evaluation of new 6-hydroxypyridazinone benzisoxazoles: potential multi-receptor-targeting atypical antipsychotics. Eur J Med Chem. 2016;124:713–728.
   PubMed Web of Science ®Google Scholar
• Koblan KS, Kent J, Hopkins SC, et al. A non–D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382:1497–1506.
   PubMed Web of Science ®Google Scholar
• Butini S, Gemma S, Campiani G, et al. 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;52:151–169.
   PubMed Web of Science ®Google Scholar
• Bhosale SH, Kanhed AM, Dash RC, et al. Design, synthesis, pharmacological evaluation and computational studies of 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics. Eur J Med Chem. 2014;74:358–365.
   PubMed Web of Science ®Google Scholar
• Zhu C, Li X, Zhao B, et al. Discovery of aryl-piperidine derivatives as potential antipsychotic agents using molecular hybridization strategy. Eur J Med Chem. 2020;193:112214.
   PubMed Web of Science ®Google Scholar
• Wróbel MZ, Chodkowski A, Marciniak M, et al. 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. 2020;97:103662.
   PubMed Web of Science ®Google Scholar
• Świerczek A, Jankowska A, Chłoń-Rzepa G, et al. Advances in the discovery of PDE10A inhibitors for CNS-related disorders. Part 2: focus on schizophrenia. Curr Drug Targets. 2019;20:1652–1669.
   PubMed Web of Science ®Google Scholar