Diterpenoids from Caribbean gorgonians act as noncompetitive inhibitors of the nicotinic acetylcholine receptor.
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.
Eterović
V A
VA
Department of Biochemistry, Universidad Central del Caribe, Bayamón, Puerto Rico 00960.
Hann
R M
RM
Ferchmin
P A
PA
Rodriguez
A D
AD
Li
L
L
Lee
Y H
YH
McNamee
M G
MG
D000818:Animals; D002460:Cell Line; D003063:Cnidaria / Q000737:chemistry*; D003064:Cnidarian Venoms / Q000494:pharmacology; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D004557:Electric Organ / Q000187:drug effects; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D018733:Nicotinic Antagonists; D009865:Oocytes / Q000187:drug effects; D009928:Organ Specificity; D010276:Parasympatholytics / Q000302:isolation & purification / Q000494:pharmacology*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013729:Terpenes; D014101:Torpedo; D014982:Xenopus laevis
C043525:12,13-bisepieupalmerin; D003064:Cnidarian Venoms; D004224:Diterpenes; D008024:Ligands; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D018733:Nicotinic Antagonists; D010276:Parasympatholytics; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D013729:Terpenes; C082582:eunicin; C082581:eupalmerin acetate; C030303:lophotoxin