Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors

Ashraf M.A. Qasem, Michael G. Rowan, Victoria R. Sanders, Neil S. Millar, Ian S. Blagbrough

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)147-157
Number of pages11
JournalACS Bio and Med Chem Au
Volume3
Issue number2
Early online date14 Feb 2023
DOIs
Publication statusPublished - 19 Apr 2023

Keywords

  • 2-methylsuccinimido benzoate ester
  • antagonist
  • human α7 nAChR
  • methyllycaconitine (MLA)
  • nicotinic acetylcholine receptors (nAChR)
  • nicotinic competitive antagonist
  • norditerpenoid alkaloid

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Pharmaceutical Science

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