Diterpenoids from Caribbean gorgonians act as noncompetitive inhibitors of the nicotinic acetylcholine receptor

• Published in: Cellular and molecular neurobiology 1993-04, Vol.13 (2), p.99-110
• Main Authors: ETEROVIC, V. A, HANN, R. M, FERCHMIN, P. A, RODRIGUEZ, A. D, LIAN LI, YUNG-HUI LEE, MCNAMEE, M. G
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; Cell receptors; Cell structures and functions; Cnidaria - chemistry; Cnidarian Venoms - pharmacology; Diterpenes - isolation & purification; Diterpenes - pharmacology; Electric Organ - drug effects; Eunicea; Fundamental and applied biological sciences. Psychology; Gorgonacea; Ligands; Marine; Mice; Molecular and cellular biology; Molecular Structure; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Muscle Proteins - antagonists & inhibitors; Muscle Proteins - genetics; Nerve Tissue Proteins - antagonists & inhibitors; Nicotinic Antagonists; Oocytes - drug effects; Organ Specificity; Parasympatholytics - isolation & purification; Parasympatholytics - pharmacology; Protein Binding; Receptors, Nicotinic - genetics; Recombinant Proteins - antagonists & inhibitors; Terpenes; Torpedo; Xenopus laevis
• ISSN: 0272-4340; 1573-6830
• DOI: 10.1007/BF00735367

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.