Thiol - reactive analogues of galanthamine , codeine and 1 morphine as potential probes to interrogate allosteric 2 binding within nAChRs
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چکیده
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 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
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