DITERPENOIDS FROM CARIBBEAN GORGONIANS ACT AS NONCOMPETITIVE INHIBITORS OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR

1. Three cyclic diterpenoids isolated from gorgonians of the Eunicea g enus and characterized as eupalmerin acetate (EUAC), 12,13-bisepieupal merin (BEEP), and eunicin (EUNI) were found to be pharmacologically ac tive on the nicotinic acetylcholine receptor (AChR). 2. The receptor f rom the BC3H-1 muscle cell line was expressed in Xenopus laevis oocyte s and studied with a two-electrode voltage clamp apparatus. 3. All thr ee compounds reversibly inhibited ACh-induced currents, with IC50's fr om 6 to 35 muM. ACh dose-response curves suggested that his inhibition was noncompetitive. The cembranoids also increased the rate of recept or desensitization. 4. Radioligand-binding studies using AChR-rich mem branes from Torpedo electric organ indicated that all three cembranoid s inhibited high-affinity [H-3]phencyclidine binding, with IC50's of 0 .8, 11.6, and 63.8 muM for EUNI, EUAC, and BEEP, respectively. The cem branoids at a 100 muM concentration did not inhibit [alpha-I-125]bunga rotoxin binding to either membrane-bound or solubilized AChR. 5. It is concluded that these compounds act as noncompetitive inhibitors of pe ripheral AChR.