Qasem, AMA;
Rowan, MG;
Sanders, VR;
Millar, NS;
Blagbrough, IS;
(2022)
Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors.
ACS Bio & Med Chem Au
10.1021/acsbiomedchemau.2c00057.
(In press).
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Abstract
Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC50 = 2 nM) selective antagonist of α7 nicotinic acetylcholine receptors (nAChRs). Several structural factors affect its activity such as the neopentyl ester side-chain and the piperidine ring N-side-chain. The synthesis of simplified AE-bicyclic analogues 14-21 possessing different ester and nitrogen side-chains was achieved in three steps. The antagonist effects of synthetic analogues were examined on human α7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced α7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 ± 1.9% compared to 3.4 ± 0.2% for MLA 1. This demonstrates that simpler analogues of MLA 1 possess antagonist effects on human α7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1.
| Type: | Article |
|---|---|
| Title: | Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acsbiomedchemau.2c00057 |
| Publisher version: | https://doi.org/10.1021/acsbiomedchemau.2c00057 |
| Language: | English |
| Additional information: | © The Authors 2022. Original content in this paper is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | antagonist, human α7 nAChR, methyllycaconitine (MLA), 2-methylsuccinimido benzoate ester, nicotinic acetylcholine receptors (nAChR), nicotinic competitive antagonist norditerpenoid alkaloid |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10165845 |
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