School of Pharmacy, University of Reading, Reading, UK.
Br J Pharmacol. 2010 Nov;161(6):1343-50. doi: 10.1111/j.1476-5381.2010.01010.x.
BACKGROUND AND PURPOSE; The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D(2) dopamine receptor in vitro.
The affinities of these compounds for the D(2) dopamine receptor were evaluated in competition with [(3) H]spiperone and [(3) H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [(35) S]GTPγS binding.
Both compounds had low affinities for inhibition of [(3) H]spiperone binding (pK(i) vs. [(3) H]spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [(35) S]GTPγS binding when assayed in the presence of Na(+) ions, but if the Na(+) ions were removed, both compounds were low-affinity, partial agonists (E(max) relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [(35) S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [(3) H]NPA dissociation from D(2) dopamine receptors, indicating some allosteric effects of this compound.
The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D(2) dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed.
This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.
背景和目的；两种苯哌啶类化合物，OSU6162 和 ACR16，由于其潜在的多巴胺稳定作用，被提议作为治疗包括精神分裂症和亨廷顿病在内的脑部疾病的新型药物。在这里，我们评估了这些化合物在一系列体外 D2 多巴胺受体测定中的活性。
通过与 [3H]spiperone 和 [3H]NPA 的竞争，评估这些化合物对 D2 多巴胺受体的亲和力。这些化合物的激动活性通过评估它们刺激 [35S]GTPγS 结合的能力来评估。
两种化合物对抑制 [3H]spiperone 结合的亲和力均较低（与 [3H]spiperone 的 pK(i)，ACR16：<5，OSU6162：5.36）。当在钠离子存在下进行测定时，这两种化合物均不能刺激 [35S]GTPγS 结合，但如果去除钠离子，这两种化合物均为低亲和力、部分激动剂（相对于多巴胺的 E(max)：ACR16：10.2%，OSU6162：54.3%）。OSU6162 抑制多巴胺刺激 [35S]GTPγS 结合的效应的 Schild 分析表明 Schild 斜率约为 0.9，表明竞争性抑制的偏差较小。然而，OSU6162 能够加速 [3H]NPA 从 D2 多巴胺受体的解离，表明该化合物具有一些变构效应。
这两种苯哌啶类化合物在体外对 D2 多巴胺受体为低亲和力、低效能的部分激动剂，可能具有一些变构效应。将它们的体外和体内效应进行比较，体外亲和力是体内效力的合理指南。然而，激动效能的体外-体内相关性仍需进一步解决。
本文是药物发现中分析受体药理学专题的一部分。要查看该部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2010.161.issue-6。
