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

Hellman, Karin LU ; Ohlsson, Jörgen LU ; Malo, Marcus ; Olsson, Roger LU and Ek, Fredrik LU (2020) In ACS Chemical Neuroscience
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... (More)

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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epub
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ACS Chemical Neuroscience
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:31850734
ISSN
1948-7193
DOI
10.1021/acschemneuro.9b00524
language
English
LU publication?
yes
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b54d94f3-ca56-4f52-8cdd-349ded323e99
date added to LUP
2020-01-10 11:41:55
date last changed
2020-01-10 15:15:45
@article{b54d94f3-ca56-4f52-8cdd-349ded323e99,
  abstract     = {<p>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.</p>},
  author       = {Hellman, Karin and Ohlsson, Jörgen and Malo, Marcus and Olsson, Roger and Ek, Fredrik},
  issn         = {1948-7193},
  language     = {eng},
  month        = {01},
  publisher    = {The American Chemical Society (ACS)},
  series       = {ACS Chemical Neuroscience},
  title        = {Discovery of Procognitive Antipsychotics by Combining Muscarinic M1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae},
  url          = {http://dx.doi.org/10.1021/acschemneuro.9b00524},
  doi          = {10.1021/acschemneuro.9b00524},
  year         = {2020},
}