Qasem Ashraf M A, Rowan Michael G, Sanders Victoria R, Millar Neil S, Blagbrough Ian S
School of Pharmacy, University of Bath, Bath BA2 7AY, U.K.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, U.K.
ACS Bio Med Chem Au. 2023 Feb 14;3(2):147-157. doi: 10.1021/acsbiomedchemau.2c00057. eCollection 2023 Apr 19.
Methyllycaconitine (MLA), , is a naturally occurring norditerpenoid alkaloid that is a highly potent (IC = 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 - 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 . The most efficacious analogue () reduced α7 nAChR agonist responses [1 nM acetylcholine (ACh)] to 53.2 ± 1.9% compared to 3.4 ± 0.2% for MLA . This demonstrates that simpler analogues of MLA 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 .
甲基lycaconitine（MLA）是一种天然存在的去甲二萜生物碱，是α7烟碱型乙酰胆碱受体（nAChRs）的高效（IC = 2 nM）选择性拮抗剂。几个结构因素会影响其活性，如新戊酯侧链和哌啶环N侧链。通过三步反应实现了具有不同酯和氮侧链的简化AE双环类似物的合成。研究了合成类似物对人α7 nAChRs的拮抗作用，并与MLA进行了比较。最有效的类似物将α7 nAChR激动剂反应[1 nM乙酰胆碱（ACh）]降低至53.2±1.9%，而MLA为3.4±0.2%。这表明MLA的更简单类似物对人α7 nAChRs具有拮抗作用，但也表明可能需要进一步优化以实现与MLA相当的拮抗活性。
