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Diterpenoids from Caribbean gorgonians act as noncompetitive inhibitors of the nicotinic acetylcholine receptor.
Eterović VA, Hann RM, Ferchmin PA, Rodriguez AD, Li L, Lee YH, McNamee MG.
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1. Three cyclic diterpenoids isolated from gorgonians of the Eunicea genus and characterized as eupalmerin acetate (EUAC), 12,13-bisepieupalmerin (BEEP), and eunicin (EUNI) were found to be pharmacologically active on the nicotinic acetylcholine receptor (AChR). 2. The receptor from the BC3H-1 muscle cell line was expressed in Xenopus laevis oocytes and studied with a two-electrode voltage clamp apparatus. 3. All three compounds reversibly inhibited ACh-induced currents, with IC50's from 6 to 35 microM. ACh dose-response curves suggested that his inhibition was noncompetitive. The cembranoids also increased the rate of receptor desensitization. 4. Radioligand-binding studies using AChR-rich membranes from Torpedo electric organ indicated that all three cembranoids inhibited high-affinity [3H]phencyclidine binding, with IC50's of 0.8, 11.6, and 63.8 microM for EUNI, EUAC, and BEEP, respectively. The cembranoids at a 100 microM concentration did not inhibit [alpha-125I]bungarotoxin binding to either membrane-bound or solubilized AChR. 5. It is concluded that these compounds act as noncompetitive inhibitors of peripheral AChR.
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