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Abstract

Structure-activity relationship for D-ring derivatives of grayanotoxin in the squid giant axon.

M Yakehiro, S Yamamoto, N Baba, S Nakajima, J Iwasa and I Seyama
Journal of Pharmacology and Experimental Therapeutics June 1993, 265 (3) 1328-1332;
M Yakehiro
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S Yamamoto
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N Baba
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S Nakajima
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J Iwasa
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I Seyama
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Abstract

Grayanotoxin (GTX) binds specifically to the voltage-dependent sodium channel and induces a persistent increase in the membrane permeability to sodium ion. By studying the structure-activity relation of the GTX action, we attempt to elucidate the molecular moiety of the sodium channel facing around the carbon atoms C-15 beta, C-16 beta and C-14S in the D-ring of GTX in exerting the biological activity. A dose-response curve for each GTX analog was constructed using membrane depolarization as an index and assuming a one-to-one stoichiometry. Addition of alpha-OH, carbonyl and beta-OH groups to either C-15 or C-16 sequentially reduces the toxin potency, suggesting that the domain of the Na channel facing C-15 and C-16 contains a positive charge. Substitution of a hydroxymethyl group to the beta side of C-16 reduces GTX activity 10 times more than a similar substitution in the alpha side, indicating that this positive charge is located close to the beta side. Introduction of a hydrophilic hydroxy group into C-14S reduced GTX activity by a factor of 20, whereas introduction of an electronegative amino group totally eliminated it. We infer that hydrophobic bonds are a predominant factor on the alpha surface of the GTX molecule. In summary, 3 beta-OH, 5 beta-OH and 6 beta-OH of the GTX molecule make contact with the Na channel by hydrogen bonding and with most of remainder by hydrophobic bond in binding to the Na channel.(ABSTRACT TRUNCATED AT 250 WORDS)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 265, Issue 3
1 Jun 1993
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Abstract

Structure-activity relationship for D-ring derivatives of grayanotoxin in the squid giant axon.

M Yakehiro, S Yamamoto, N Baba, S Nakajima, J Iwasa and I Seyama
Journal of Pharmacology and Experimental Therapeutics June 1, 1993, 265 (3) 1328-1332;

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Abstract

Structure-activity relationship for D-ring derivatives of grayanotoxin in the squid giant axon.

M Yakehiro, S Yamamoto, N Baba, S Nakajima, J Iwasa and I Seyama
Journal of Pharmacology and Experimental Therapeutics June 1, 1993, 265 (3) 1328-1332;
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