title: Diterpenoids from Caribbean gorgonians act as noncompetitive inhibitors of the nicotinic acetylcholine receptor.
abstract: 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.
authors.affiliation: Department of Biochemistry, Universidad Central del Caribe, Bayamón, Puerto Rico 00960.
authors.forename: V A
authors.initials: VA
authors.lastname: Eterović
authors.forename: R M
authors.initials: RM
authors.lastname: Hann
authors.forename: P A
authors.initials: PA
authors.lastname: Ferchmin
authors.forename: A D
authors.initials: AD
authors.lastname: Rodriguez
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: Y H
authors.initials: YH
authors.lastname: Lee
authors.forename: M G
authors.initials: MG
authors.lastname: McNamee
mesh_terms: 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
chemical_list: 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