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Untreated schizophrenia leads to deterioration in quality of life and premature death. Although the clinical efficacy of dopamine D2 receptor antagonists against positive symptoms of schizophrenia supports the dopamine hypothesis of the disease, the resistance of negative and cognitive symptoms to these drugs implicates other systems in its pathophysiology. Many studies suggest that abnormalities in glutamate homeostasis may contribute to all three groups of schizophrenia symptoms. Scientific considerations also include disorders of gamma-aminobutyric acid-ergic and serotonergic neurotransmissions as well as the role of the immune system. The purpose of this review is to update the most recent reports on the discovery and development of non-dopaminergic agents that may reduce positive, negative, and cognitive symptoms of schizophrenia, and may be alternative to currently used antipsychotics. This review collects the chemical structures of representative compounds targeting metabotropic glutamate receptor, gamma-aminobutyric acid type A receptor, alpha 7 nicotinic acetylcholine receptor, glycine transporter type 1 and glycogen synthase kinase 3 as well as results of in vitro and in vivo studies indicating their efficacy in schizophrenia. Results of clinical trials assessing the safety and efficacy of the tested compounds have also been presented. Finally, attention has been paid to multifunctional ligands with serotonin receptor affinity or phosphodiesterase inhibitory activity as novel strategies in the search for dedicated medicines for patients with schizophrenia.<\/jats:p><\/jats:sec>","DOI":"10.2174\/0929867326666190710172002","type":"journal-article","created":{"date-parts":[[2019,7,11]],"date-time":"2019-07-11T09:57:30Z","timestamp":1562839050000},"page":"4885-4913","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Discovery and Development of Non-Dopaminergic Agents for the Treatment of Schizophrenia: Overview of the Preclinical and Early Clinical Studies"],"prefix":"10.2174","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-7609","authenticated-orcid":true,"given":"Agnieszka","family":"Jankowska","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0756-7232","authenticated-orcid":true,"given":"Grzegorz","family":"Sata\u0142a","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9606-5228","authenticated-orcid":true,"given":"Anna","family":"Partyka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2383-3278","authenticated-orcid":true,"given":"Anna","family":"Weso\u0142owska","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1417-6333","authenticated-orcid":true,"given":"Andrzej J.","family":"Bojarski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2445-9759","authenticated-orcid":true,"given":"Maciej","family":"Paw\u0142owski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-7801","authenticated-orcid":true,"given":"Gra\u017cyna","family":"Ch\u0142o\u0144-Rzepa","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"965","reference":[{"key":"ref=1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s40501-014-0010-9","volume":"1","author":"Javitt D.C.","year":"2015","unstructured":"Javitt D.C.; Current and emergent treatments for symptoms and neurocognitive impairment in schizophrenia. 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