{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T02:06:13Z","timestamp":1788746773857,"version":"build-2803163510"},"reference-count":216,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T00:00:00Z","timestamp":1643414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry for University and Research","award":["20175SA5JJ"],"award-info":[{"award-number":["20175SA5JJ"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Polypharmacology breaks up the classical paradigm of \u201cone-drug, one target, one disease\u201d electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson\u2019s disease (PD), Alzheimer\u2019s disease (AD), Huntington\u2019s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.<\/jats:p>","DOI":"10.3390\/cells11030471","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T23:02:06Z","timestamp":1643497326000},"page":"471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-3648","authenticated-orcid":false,"given":"Alessandro","family":"Papa","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9442-1428","authenticated-orcid":false,"given":"Silvia","family":"Pasquini","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3936-5923","authenticated-orcid":false,"given":"Chiara","family":"Contri","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8313-2417","authenticated-orcid":false,"given":"Sandra","family":"Gemma","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Campiani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-0880","authenticated-orcid":false,"given":"Stefania","family":"Butini","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4562-1348","authenticated-orcid":false,"given":"Katia","family":"Varani","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5027-1699","authenticated-orcid":false,"given":"Fabrizio","family":"Vincenzi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrn3876","article-title":"Endocannabinoid Signalling and the Deteriorating Brain","volume":"16","author":"Stella","year":"2015","journal-title":"Nat. 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