Discovery of Procognitive Antipsychotics by Combining Muscarinic M1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae

Research output: Contribution to journalArticle

Abstract

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N-Desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M1 receptor (M1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesized to establish a structure-activity relationship (SAR) at the M1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M1 agonist activity was established by functionalization in the 4- and 8-positions in the tricyclic core. In vivo behavioral response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M1 agonist activity. Cotreatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f, in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential procognitive activity.

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Authors
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External organisations
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)173-183
Number of pages11
JournalACS Chemical Neuroscience
Volume11
Issue number2
Early online date2020 Jan 3
Publication statusPublished - 2020 Jan 15
Publication categoryResearch
Peer-reviewedYes