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Investigation Into Novel Mukanadin B, Mukanadin D and Mukanadin F Derivatives as Antagonists of 5-HT 1A Signalling.
- Source :
-
ChemMedChem [ChemMedChem] 2024 Aug 01; Vol. 19 (15), pp. e202400102. Date of Electronic Publication: 2024 Jun 05. - Publication Year :
- 2024
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Abstract
- Marine bromopyrrole alkaloids are a diverse family of natural products with a large array of biological applications. The mukanadin family is a group of molecules consisting of seven members (mukanadin A-G) that possess a range of biological activities. Inhibition of serotonergic signaling has been demonstrated by mukanadin B derivatives, presenting this chemical scaffold as a candidate for further SAR exploration. A library of thirteen novel mukanadin B and D derivatives with structural variation targeted at the pyrrole ring, central linker and hydantoin ring, were synthesized. These analogues were subsequently assessed for serotonergic antagonism, in addition to natural products, mukanadin B, D, F and 9-hydroxy mukanadin B. A collection of compounds exhibited significant 5-HT <subscript>1A</subscript> signaling, including five of the novel derivatives and two of the naturally occurring bromopyrroles, mukanadin B and F. Particular SAR information could be determined from these results, such as modification of the pyrrole ring being a well-tolerated strategy for improving serotonergic inhibition. Other changes to the pharmacophore led to significant reduction in activity such as saturation of the linker region, or no conclusive improvement in inhibitory activity such as a 9-OH group or replacement of the hydantoin ring with a triazole moiety.<br /> (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
- Subjects :
- Structure-Activity Relationship
Humans
Molecular Structure
Animals
Serotonin 5-HT1 Receptor Antagonists pharmacology
Serotonin 5-HT1 Receptor Antagonists chemistry
Serotonin 5-HT1 Receptor Antagonists chemical synthesis
Dose-Response Relationship, Drug
Pyrroles pharmacology
Pyrroles chemistry
Pyrroles chemical synthesis
Signal Transduction drug effects
Receptor, Serotonin, 5-HT1A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 19
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 38661010
- Full Text :
- https://doi.org/10.1002/cmdc.202400102