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Discovery of Procog...
Discovery of Procognitive Antipsychotics by Combining Muscarinic M-1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae
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- Hellman, Karin (författare)
- Lund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups
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- Ohlsson, Jörgen (författare)
- Lund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups
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- Malo, Marcus (författare)
- University of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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- Olsson, Roger, 1967 (författare)
- University of Gothenburg,Lund University,Lunds universitet,Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,NanoLund: Centre for Nanoscience,Annan verksamhet, LTH,Lunds Tekniska Högskola,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Other operations, LTH,Faculty of Engineering, LTH,Chemical Biology and Therapeutics,Lund University Research Groups,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Ek, Fredrik (författare)
- Lund University,Lunds universitet,NanoLund: Centre for Nanoscience,Annan verksamhet, LTH,Lunds Tekniska Högskola,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Other operations, LTH,Faculty of Engineering, LTH,Chemical Biology and Therapeutics,Lund University Research Groups
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(creator_code:org_t)
- 2019-12-18
- 2020
- Engelska.
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 11:2, s. 173-183
- Relaterad länk:
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http://dx.doi.org/10...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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Abstract
Ämnesord
Stäng
- 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-1 receptor (M-1) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M-1 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-1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M-1 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-1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M-1 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Nyckelord
- Zebrafish
- antipsychotics
- muscarinic agonist
- structure-activity
- relationship
- N-desmethylclozapine
- behavioral profiling
- n-desmethylclozapine
- allosteric modulation
- drug
- schizophrenia
- clozapine
- m1
- identification
- association
- impairment
- activation
- Biochemistry & Molecular Biology
- Pharmacology & Pharmacy
- Neurosciences
- & Neurology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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