@article{discovery10165845,
            note = {{\copyright} 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/).},
       publisher = {American Chemical Society (ACS)},
           month = {February},
            year = {2022},
           title = {Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human {\ensuremath{\alpha}}7 Nicotinic Acetylcholine Receptors},
         journal = {ACS Bio \& Med Chem Au},
             url = {https://doi.org/10.1021/acsbiomedchemau.2c00057},
          author = {Qasem, AMA and Rowan, MG and Sanders, VR and Millar, NS and Blagbrough, IS},
        abstract = {Methyllycaconitine (MLA), 1, is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC50 = 2 nM) selective antagonist of {\ensuremath{\alpha}}7 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 {\ensuremath{\alpha}}7 nAChRs and compared to that of MLA 1. The most efficacious analogue (16) reduced {\ensuremath{\alpha}}7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 {$\pm$} 1.9\% compared to 3.4 {$\pm$} 0.2\% for MLA 1. This demonstrates that simpler analogues of MLA 1 possess antagonist effects on human {\ensuremath{\alpha}}7 nAChRs but also indicates that further optimization may be possible to achieve antagonist activity comparable to that of MLA 1.},
        keywords = {antagonist, human {\ensuremath{\alpha}}7 nAChR, methyllycaconitine (MLA), 2-methylsuccinimido benzoate ester, nicotinic acetylcholine receptors (nAChR), nicotinic competitive antagonist norditerpenoid alkaloid}
}