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- Hellman, KarinLund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups (author)
Discovery of Procognitive Antipsychotics by Combining Muscarinic M-1 Receptor Structure-Activity Relationship with Systems Response Profiles in Zebrafish Larvae
- Article/chapterEnglish2020
Publisher, publication year, extent ...
- 2019-12-18
- American Chemical Society (ACS),2020
Numbers
- LIBRIS-ID:oai:gup.ub.gu.se/290252
- https://gup.ub.gu.se/publication/290252URI
- https://doi.org/10.1021/acschemneuro.9b00524DOI
- https://lup.lub.lu.se/record/b54d94f3-ca56-4f52-8cdd-349ded323e99URI
Supplementary language notes
- Language:English
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- SwePubSwePub
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Notes
- 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.
Subject headings and genre
- 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
- 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
Added entries (persons, corporate bodies, meetings, titles ...)
- Ohlsson, JörgenLund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups(Swepub:lu)orgk-joh (author)
- Malo, MarcusUniversity of Gothenburg,Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xmalom (author)
- Olsson, Roger,1967University 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(Swepub:lu)med-reo (author)
- Ek, FredrikLund 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(Swepub:lu)orgk1-fe (author)
- Kemisk biologi med inriktning mot läkemedelsutvecklingForskargrupper vid Lunds universitet (creator_code:org_t)
Related titles
- In:ACS Chemical Neuroscience: American Chemical Society (ACS)11:2, s. 173-1831948-7193
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