Alkondon M, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, USA.
J Pharmacol Exp Ther. 1995 Aug;274(2):771-82.
The nicotinic-agonist properties of epibatidine, an alkaloid originally isolated from the Ecuadorian frog Epipedobates tricolor, was investigated in rat hippocampal neurons grown in culture. The ability of epibatidine enantiomers to evoke nicotinic whole-cell currents of type IA, sensitive to blockade by alpha-bungaro-toxin and methyllycaconitine and presumably subserved by an alpha-7-based nAChR, and of type II, sensitive to blockade by dihydro-beta-erythroidine and presumably subserved by an alpha 4 beta 2-based nAChR, was studied and compared with that of other nicotinic agonists. Epibatidine elicited type IA currents with EC50 values of 2.9 and 4.3 microM for the (-)- and (+)- enantiomers, respectively. The potency of the agonists in evoking type IA currents was as follows: (-)-epibatidine > (+)- anatoxin-a > (+)-epibatidine > (-)-nicotine > DMPP > cytisine > acetylcholine. The EC50 values of (-)- and (+)- epibatidine in eliciting type II currents were 19 and 15 nM, respectively. The order of potency of the agonists in evoking type II currents was: (+)-epibatidine > (-)-epibatidine > cytisine > (+)-anatoxin-a > (-)-nicotine > acetylcholine > DMPP. Although these agonists produced nearly identical maximal type IA responses, the size of the maximal type II responses varied with the agonist. Cytisine and (+)-anatoxin-a were the least efficacious agonists in inducing type II currents. Enantiomers of epibatidine showed the least stereoselectivity, those of nicotine showed a moderate stereoselectivity, and those of anatoxin-a exhibited the highest stereoselectivity in inducing either type of currents. In summary, these results suggest that epibatidine can be used as a novel nicotinic agonist for the study of type II currents, and that the nicotinic acetylcholine receptor related to type II currents may be one of the key target sites through which agonists such as epibatidine and nicotine elicit their behavioral actions in vivo.
从厄瓜多尔三色箭毒蛙（Epipedobates tricolor）中最初分离出的生物碱埃皮巴蒂啶（epibatidine）的烟碱样激动剂特性，在培养的大鼠海马神经元中进行了研究。研究了埃皮巴蒂啶对映体诱发IA型烟碱全细胞电流的能力，该电流对α-银环蛇毒素（alpha-bungaro-toxin）和甲基lycaconitine的阻断敏感，推测由基于α-7的烟碱乙酰胆碱受体（nAChR）介导；以及诱发II型烟碱全细胞电流的能力，该电流对二氢β-刺桐啶（dihydro-beta-erythroidine）的阻断敏感，推测由基于α4β2的nAChR介导，并与其他烟碱样激动剂进行了比较。埃皮巴蒂啶对（-）-和（+）-对映体诱发IA型电流的EC50值分别为2.9和4.3 microM。激动剂诱发IA型电流的效力如下：（-）-埃皮巴蒂啶>（+）-anatoxin-a>（+）-埃皮巴蒂啶>（-）-尼古丁>DMPP>金雀花碱>乙酰胆碱。（-）-和（+）-埃皮巴蒂啶诱发II型电流的EC50值分别为19和15 nM。激动剂诱发II型电流的效力顺序为：（+）-埃皮巴蒂啶>（-）-埃皮巴蒂啶>金雀花碱>（+）-anatoxin-a>（-）-尼古丁>乙酰胆碱>DMPP。尽管这些激动剂产生的最大IA型反应几乎相同，但最大II型反应的大小因激动剂而异。金雀花碱和（+）-anatoxin-a是诱导II型电流中效力最低的激动剂。在诱发任何一种类型的电流时，埃皮巴蒂啶的对映体表现出最小的立体选择性，尼古丁的对映体表现出中等的立体选择性，而anatoxin-a的对映体表现出最高的立体选择性。总之，这些结果表明，埃皮巴蒂啶可作为研究II型电流的新型烟碱样激动剂，并且与II型电流相关的烟碱乙酰胆碱受体可能是埃皮巴蒂啶和尼古丁等激动剂在体内引发其行为作用的关键靶位点之一。
