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

doi:10.1021/acsbiomedchemau.2c00057

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

Department of Life Sciences

University College London

Research output: Contribution to journal › Article › peer-review

5 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 language	English
Pages (from-to)	147-157
Number of pages	11
Journal	ACS Bio and Med Chem Au
Volume	3
Issue number	2
Early online date	14 Feb 2023
DOIs	https://doi.org/10.1021/acsbiomedchemau.2c00057
Publication status	Published - 19 Apr 2023

Funding

We acknowledge Zarqa University, Jordan, for funding the studentship of Ashraf M. A. Qasem, and a BBSRC Industrial CASE PhD studentship associated with the London Interdisciplinary Doctoral Program (LIDo) and in collaboration with Syngenta [Grant BB/M009513/1] awarded to Victoria R. Sanders.

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

Access to Document

10.1021/acsbiomedchemau.2c00057Licence: CC BY

Cite this

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title = "Synthesis and Antagonist Activity of Methyllycaconitine Analogues on Human α7 Nicotinic Acetylcholine Receptors",

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.",

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AU - Millar, Neil S.

AU - Blagbrough, Ian S.

PY - 2023/4/19

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AB - 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.

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

Abstract

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Keywords

ASJC Scopus subject areas

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Equipment

Avance III 500 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (9West)

Avance NEO 500 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (1South)

Cite this