Thiol-Reactive Analogues of Galanthamine, Codeine, and Morphine as Potential Probes to Interrogate Allosteric Binding within Nicotinic Acetylcholine Receptors

Ryan Gallagher; Mary Chebib; Thomas Balle; Malcolm D. McLeod

doi:10.1071/CH15475

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Thiol-Reactive Analogues of Galanthamine, Codeine, and Morphine as Potential Probes to Interrogate Allosteric Binding within Nicotinic Acetylcholine Receptors

Ryan Gallagher ^A , Mary Chebib ^B , Thomas Balle ^B and Malcolm D. McLeod ^A ^C

+ Author Affiliations

- Author Affiliations

^A Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.

^B Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.

^C Corresponding author. Email: malcolm.mcleod@anu.edu.au

Australian Journal of Chemistry 68(12) 1834-1841 https://doi.org/10.1071/CH15475
Submitted: 6 August 2015 Accepted: 7 September 2015 Published: 6 October 2015

Abstract

Alkaloids including galanthamine (1) and codeine (2) are reported to be positive allosteric modulators of nicotinic acetylcholine receptors (nAChRs), but the binding sites responsible for this activity are not known with certainty. Analogues of galanthamine (1), codeine (2), and morphine (3) with reactivity towards cysteine thiols were synthesized including conjugated enone derivatives of the three alkaloids 4–6 and two chloro-alkane derivatives of codeine 7 and 8. The stability of the enones was deemed sufficient for use in buffered aqueous solutions, and their reactivity towards thiols was assessed by determining the kinetics of reaction with a cysteine derivative. All three enone derivatives were of sufficient reactivity and stability to be used in covalent trapping, an extension of the substituted cysteine accessibility method, to elucidate the allosteric binding sites of galanthamine and codeine at nAChRs.

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Thiol-Reactive Analogues of Galanthamine, Codeine, and Morphine as Potential Probes to Interrogate Allosteric Binding within Nicotinic Acetylcholine Receptors

Abstract

References

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