{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:03:03Z","timestamp":1790265783456,"version":"4.1.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T00:00:00Z","timestamp":1487635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T00:00:00Z","timestamp":1487635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions. Here, we identified candidate biomolecules contributing to the organic basis for psychosis by deriving an <jats:italic>in vivo<\/jats:italic> biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel <jats:italic>in silico<\/jats:italic> approach identifies the ensemble of potential drug targets based on the drug\u2019s chemical structure and the region-specific gene expression profile of each target in the central nervous system. We subtracted the signature of the action of clozapine from that of a typical antipsychotic, chlorpromazine. Our results implicate dopamine D4 receptors in the pineal gland and muscarinic acetylcholine M1 (CHRM1) and M3 (CHRM3) receptors in the prefrontal cortex (PFC) as significant and unique to clozapine, whereas serotonin receptors 5-HT<jats:sub>2A<\/jats:sub> in the PFC and 5-HT<jats:sub>2C<\/jats:sub> in the caudate nucleus were common significant sites of action for both drugs. Our results suggest that D4 and CHRM1 receptor activity in specific tissues may represent underappreciated drug targets to advance the pharmacologic treatment of schizophrenia. These findings may enhance our understanding of the organic basis of psychiatric disorders and help developing effective therapies.<\/jats:p>","DOI":"10.1038\/tp.2017.6","type":"journal-article","created":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T15:39:27Z","timestamp":1487691567000},"page":"e1036-e1036","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Chemistry-based molecular signature underlying the atypia of clozapine"],"prefix":"10.1038","volume":"7","author":[{"given":"T","family":"Cardozo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Shmelkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Felsovalyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Swetnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Malaspina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S V","family":"Shmelkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,21]]},"reference":[{"key":"BFtp20176_CR1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1601-183X.2005.00186.x","volume":"5","author":"TD Gould","year":"2006","unstructured":"Gould TD, Gottesman II . 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TC is a founder and a shareholder of GeneCentrix. This work was supported by NIH grant RC LM010994 from the National Library of Medicine to TC. ES is a named inventor on a patent (\u2018Method of Identifying the molecular basis of the activity of a drug compound, pharmaceutical compositions, and treatment methods.\u2019 US Patent Application #14\/538,950). SVS is a founder and a shareholder of GeneCentrix. No funding was received from GeneCentrix for the present study. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}