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
2015 Australian journal of chemistry (Print)  
16 Alkaloids including galanthamine (1) and codeine (2) are reported to be positive allosteric 17 modulators of nicotinic acetylcholine receptors (nAChRs) but the binding sites responsible 18 for this activity are not known with certainty. Analogues of galanthamine (1), codeine (2) and 19 morphine (3) with reactivity towards cysteine thiols were synthesised including conjugated 20 enone derivatives of the three alkaloids 4-6 and two chloro-alkane derivatives of codeine 7 21 and 8. The stability
more » ... nd 8. The stability of the enones was deemed sufficient for use in buffered aqueous solutions 22 and their reactivity towards thiols was assessed by determining the kinetics of reaction with a 23 cysteine derivative. All three enone derivatives were of sufficient reactivity and stability to be 24 used in covalent trapping, an extension of the substituted cysteine accessibility method 25 (SCAM), to elucidate the allosteric binding sites of galanthamine and codeine at nAChRs. 26 27
doi:10.1071/ch15475 fatcat:4pttwv2njfhozi2zflctta7ki4