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-HT2A in the PFC and 5-HT2C 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.

The Analgesic Acetaminophen and the Antipsychotic Clozapine Can Each Redox-Cycle with Melanin

“…Interestingly recent reports indicate that acetaminophen has underappreciated antioxidant properties and at low doses can have protective effects against oxidative stress-induced brain toxicity and neurodegeneration . The second drug, clozapine (CLZ), is a second generation antipsychotic and considered to be a preeminent example of serendipitous polypharmacology in that it appears to be a broad spectrum ligand capable of interacting with multiple target receptors . However, there remains considerable controversy regarding clozapine’s unique efficacy and profile …”

“…42 The second drug, clozapine (CLZ), is a second generation antipsychotic and considered to be a preeminent example of serendipitous polypharmacology in that it appears to be a broad spectrum ligand 43 capable of interacting with multiple target receptors. 44 However, there remains considerable controversy regarding clozapine's unique efficacy and profile. 43 ■ RESULTS AND DISCUSSION Characterization of Natural and Synthetic Melanins.…”

Molecular basis of atypicality of bupropion inferred from its receptor engagement in nervous system tissues

“…The methods used in this study were previously described in a case study consisting of historeceptomic analysis of several schizophrenia drugs (Cardozo et al 2017 ).…”

“…Previously, we developed a novel in silico method for inferring, in vivo, the molecular target engagement signature of the MOA of drugs and applied it to a case study of the atypical antipsychotic drug clozapine (Shmelkov et al 2015 ; Cardozo et al 2017 ). This “historeceptomic” (HR) method integrates the affinities between a given drug and its complete ensemble of protein targets with the transcriptional levels of those targets in tissues of the body.…”

Επιδράσεις των IFNs - αντιψυχωσικών στον κυτταρικό κύκλο και θάνατο σε κυτταρικές σειρές γλοιοβλαστώματος σε συνδιασμό με χημειοθεραπευτικά

“…Η ρισπεριδόνη έχει πολύ χαμηλότερη συγγένεια για το υποδοχέα α2 από την κλοζαπίνη, αλλά ελαφρώς υψηλότερη συγγένεια από τα άλλα άτυπα αντιψυχωσικά (232). Ο ανταγωνισμός του α2 υποδοχέα από την κλοζαπίνη και της νορκουετιαπίνη μπορεί να είναι σημαντική για τα αντικαταθλιπτικά χαρακτηριστικά τους και αυτό το αποτέλεσμα θα μπορούσε να εξηγήσει εν μέρει την ανωτερότητα της κλοζαπίνης στην πρόληψη της αυτοκτονίας (233). Μικρός αποκλεισμός ντοπαμινεργικών υποδοχέων D2 με ισχυρό ανταγωνιστή του υποδοχέα α2 φαίνεται να είναι ένα καλό προφίλ για ένα νευροληπτικό φάρμακο, και αυτό θα μπορούσε να είναι μια άλλη ιδιαιτερότητα του μηχανισμού δράσης της κλοζαπίνης (232).…”