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There are a number of antidepressant drugs on the market, but treatment\u2010resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine\u2010based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine\u2010based therapeutic agents in early\u2010 or late\u2010phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine\u2010based antidepressants.<\/jats:p>","DOI":"10.1002\/cmdc.202100045","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T05:37:35Z","timestamp":1615354655000},"page":"1878-1901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure\u2010Activity Relationships"],"prefix":"10.1002","volume":"16","author":[{"given":"Ravi Ranjan","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry ISF College of Pharmacy  Ghal Kalan, G.T Road Moga Punjab 142001 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Sahu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry ISF College of Pharmacy  Ghal Kalan, G.T Road Moga Punjab 142001 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9563-3382","authenticated-orcid":false,"given":"Shelly","family":"Pathania","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry ISF College of Pharmacy  Ghal Kalan, G.T Road Moga Punjab 142001 India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4774-6358","authenticated-orcid":false,"given":"Pankaj Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Integrative Physiology and Pharmacology Institute of Biomedicine Faculty of Medicine University of Turku  20520 Turku Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9460-5304","authenticated-orcid":false,"given":"M. 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