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The lophotoxins are naturally occurring antagonists of nicotinic acetylcholine receptors. These toxins are small diterpenes that irreversibly inhibit nicotinic receptors by specific covalent modification of Tyr190 in the alpha-subunits of the receptor. The naturally occurring lophotoxin analogs, bipinnatin-A and -C, are inactive protoxins. Activation of these toxins occurs spontaneously in buffer and involves replacement of the C2 acetate ester with a hydroxyl group. The mechanism involved in conversion of the inactive bipinnatins into their biologically active solvolysis products was investigated in this study. Solvolysis of bipinnatin-A in buffer containing [18O]water demonstrated that the C2 hydroxyl of the biologically active solvolysis product originated from the solvent. The rates of solvolysis of bipinnatins-A and -C were not affected by sodium azide. However, in the presence of azide, solvent products decreased and new azide-containing products appeared. Thus azide acted as a nucleophile after a rate-limiting step, such as the formation of a carbocation intermediate. The kaz/ks values for bipinnatin-A (2900 M-1) and bipinnatin-C (1450 M-1) suggest that the carbocation intermediates are relatively stable. Compounds capable of spontaneously generating carbocations may represent a novel new class of active-site-directed affinity reagents that can be applied to other receptors and enzymes.


E G Hyde, S M Thornhill, A J Boyer, S N Abramson. Evidence for a carbocation intermediate during conversion of bipinnatin-A and -C into irreversible inhibitors of nicotinic acetylcholine receptors. Journal of medicinal chemistry. 1995 Nov 10;38(23):4704-9

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PMID: 7473598

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