Ring-fused 3β-acetoxyandrost-5-enes as novel neuroprotective agents with cholinesterase inhibitory properties
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
36162631
DOI
10.1016/j.jsbmb.2022.106194
PII: S0960-0760(22)00145-5
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase and butyrylcholinesterase enzymes, Cholinesterase inhibitors, Hexacyclic steroids, Neuroprotective agents, Steroidal N-sulfonyl-1-azadiene,
- MeSH
- Acetylcholinesterase metabolism therapeutic use MeSH
- Alzheimer Disease * drug therapy metabolism MeSH
- Androstanes chemistry pharmacology MeSH
- Butyrylcholinesterase metabolism therapeutic use MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Humans MeSH
- Neuroprotective Agents * pharmacology therapeutic use MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Androstanes MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Neuroprotective Agents * MeSH
Alzheimer´s disease (AD) is an intellectual disorder caused by organic brain damage and cerebral atrophy, characterized by the loss of memory, judgment, and abstract thinking followed by declining cognitive functions, language, and the ability to perform daily living activities. Many efforts have been made to decrease the effects of the disease but also to block the neurodegenerative process. Cholinesterase inhibitors (ChEIs) are a group of medicines that act at the neurotransmission of acetylcholine, preventing its excessive breakdown and helping to improve cognitive functions in patients with AD. In this work, 16 chiral steroids, namely ring-fused 3β-acetoxyandrost-5-ene derivatives, their precursor and two 16-dehydroprogesterone-derived dioximes, were assessed as cholinesterase inhibitors and neuroprotective agents. The results demonstrated that some of the tested steroids are cholinesterase inhibitors and the majority selective for acetylcholinesterase inhibition. Albeit, one ring-fused 3β-acetoxyandrost-5-ene containing N-methylpiperidine ring (compound 2g) demonstrated to be a selective and potent inhibitor of the butyrylcholinesterase enzyme. (S)- 4,4a,5,6,7,8-(hexahydronaphthalen-2-one)-fused 3β-acetoxyandrost-5-ene (compound 6) showed high neuroprotective effect, high ability to restore the mitochondrial membrane potential from glutamate intoxication, and dramatic improvement in cell morphology. The described results provided relevant structure-activity relationship data.
References provided by Crossref.org
