Mihalak Karla B, Carroll F Ivy, Luetje Charles W
Department of Molecular and Cellular Pharmacology (R-189), University of Miami Miller School of Medicine, PO Box 016189, Miami, FL 33101, USA.
Mol Pharmacol. 2006 Sep;70(3):801-5. doi: 10.1124/mol.106.025130. Epub 2006 Jun 9.
Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of alpha4beta2 receptors, and in equilibrium binding assays, it is highly selective for the alpha4beta2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at alpha4beta2 receptors, with an EC50 of 2.3 +/- 0.3 microM and an efficacy (relative to acetylcholine) of 13.4 +/- 0.4%. Varenicline has lower potency and higher efficacy at alpha3beta4 receptors, with an EC50 of 55 +/- 8 microM and an efficacy of 75 +/- 6%. Varenicline also seems to be a weak partial agonist at alpha3beta2 and alpha6-containing receptors, with an efficacy <10%. It is remarkable that varenicline is a potent, full agonist at alpha7 receptors with an EC50 of 18 +/- 6 microM and an efficacy of 93 +/- 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric alpha7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.
伐尼克兰是一种基于金雀花碱结构的新型烟碱配体，最近已获美国食品药品监督管理局批准用作戒烟辅助药物。伐尼克兰已被证明是α4β2受体的部分激动剂，在平衡结合试验中，它对α4β2受体具有高度选择性。在本研究中，我们检测了伐尼克兰在非洲爪蟾卵母细胞中表达的多种大鼠神经元烟碱受体上的功能活性，并在双电极电压钳下进行测定。我们还发现，伐尼克兰是α4β2受体的强效部分激动剂，EC50为2.3±0.3微摩尔，效能（相对于乙酰胆碱）为13.4±0.4%。伐尼克兰对α3β4受体的效力较低但效能较高，EC50为55±8微摩尔，效能为75±6%。伐尼克兰似乎也是α3β2和含α6受体的弱部分激动剂，效能<10%。值得注意的是，伐尼克兰是α7受体的强效完全激动剂，EC50为18±6微摩尔，效能为93±7%（相对于乙酰胆碱）。因此，虽然伐尼克兰在一些异聚体神经元烟碱受体上是部分激动剂，但在同聚体α7受体上是完全激动剂。这些作用的某种组合可能参与了伐尼克兰作为戒烟辅助药物的作用机制。
