title: Chemistry-based molecular signature underlying the atypia of clozapine.
abstract: 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 in vivo biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel in silico approach identifies the ensemble of potential drug targets based on the drug's 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-HT2Ain the PFC and 5-HT2Cin 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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Shmelkov
authors.affiliation: GeneCentrix Inc., New York, NY, USA.
authors.forename: K
authors.initials: K
authors.lastname: Felsovalyi
authors.affiliation: Google Inc., Mountain View, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Swetnam
authors.affiliation: Department of Neurology, NYU School of Medicine, New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Butler
authors.affiliation: Department of Psychiatry, NYU School of Medicine, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Department of Psychiatry, NYU School of Medicine, New York, NY, USA.|Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Shmelkov
mesh_terms: D014150:Antipsychotic Agents / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002421:Caudate Nucleus / Q000378:metabolism; D002746:Chlorpromazine / Q000378:metabolism*; D003024:Clozapine / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D010870:Pineal Gland / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; C086088:CHRM1 protein, human; C000595896:CHRM3 protein, human; C493599:DRD4 protein, human; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D050638:Receptors, Dopamine D4; D003024:Clozapine; D002746:Chlorpromazine