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Discovery of Procognitive Antipsychotics by Combining Muscarinic M 1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2020 Jan 15; Vol. 11 (2), pp. 173-183. Date of Electronic Publication: 2020 Jan 03. - Publication Year :
- 2020
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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 M <subscript>1</subscript> receptor (M <subscript>1</subscript> ) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M <subscript>1</subscript> 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 M <subscript>1</subscript> receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M <subscript>1</subscript> 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 M <subscript>1</subscript> activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M <subscript>1</subscript> 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.
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 11
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 31850734
- Full Text :
- https://doi.org/10.1021/acschemneuro.9b00524