THE COCAINE RECEPTOR--STRUCTURE/ACTIVITY RELATIONSHIPS AND LIGAND BINDING

这个项目的目标是多方面的。其中一个目标是研究 可卡因及其类似物的构效关系 它与转运体的结合。更有力的类比显然是 与体外和体内结合配体一样有用。还有，这就是 成为我们工作的更大部分，其中许多化合物相当 可能是有用的替代激动剂药物，很像美沙酮 或者尼古丁贴片，在人类精神刺激滥用者身上。 我们发表了两项关于新型可卡因类似物及其能力的新研究 与多巴胺转运体结合。酰胺类似物(在C2位置) 对多巴胺转运体具有高度的效力和高度的选择性。 这是另一组具有这些性质的化合物。 不幸的是，在实验中，我们已经标记了各种有效和 选择性含酰胺的可卡因类似物，我们发现当它们 他们在体外很好地结合了多巴胺转运体的配体 不能穿过血脑屏障，也不能在体内使用 作为结合配体或行为活性探针。一系列定量构效关系 对各种可卡因类似物的研究扩展了我们从 结构-活性工作中获得的结合数据和阐明的特征 可卡因的药效团。这些研究还提供了有趣的 关于新型类似物的预测性信息。因此，更多的化合物 将使用计算来合成。 RTI-121是一种高效、选择性的多巴胺转运蛋白抑制剂。 我们团队的研究人员以放射性标记的形式制作了化合物 正如结合数据所预测的那样，它是一种极好的 体外结合化合物。它具有很高的亲和力，对 转运蛋白，并具有与结合完全一致的药理 多巴胺转运体。这种化合物不仅可用于 体外，也可以在体内作为PET或SPECT的配体。似乎有一种 对这种物质非常感兴趣，我们预计它将成为 相当频繁地使用配基。 我们继续寻找新的类比。艾薇·卡罗尔博士，化学家 监督合成工作，继续热衷于此 项目。

The goal of this project is multifold. One goal is to study the structure-activity relationships of cocaine and its analogs in terms of its binding to the transporter. The more potent analogs are obviously useful as in vitro and in vivo binding ligands. Also, and this is becoming a bigger part of our work, many of these compounds are quite possibly useful as substitute agonist medications, much like methadone or the nicotine patch, in human psychostimulant abusers. We published two new studies on novel cocaine analogs and their ability to bind to the dopamine transporter. Amide analogs (in the C2 position) are highly potent and highly selective for the dopamine transporter. This is yet another group of compounds that have these properties. Unfortunately, in experiments where we've radiolabeled various potent and selective amide-containing cocaine analogs, we found that while they were excellent in vitro binding ligands for the dopamine transporter, they did not cross the blood-brain barrier and could not be used in vivo, either as binding ligands or as behaviorally active probes. A series of QSAR studies of a variety of cocaine analogs extended our knowledge from the binding data obtained in structure-activity work and elucidated features of the cocaine pharmacophore. These studies also provide interesting predictive information about novel analogs. Thus, additional compounds will be synthesized using the calculations. RTI-121 is a potent and selective dopamine transporter inhibitor. Investigators from our team made the compound in a radiolabeled form and showed, as predicted by the binding data, that it is an excellent in vitro binding compound. It had high affinity, was selective for the transporter, and had a pharmacology completely consistent with binding to the dopamine transporter. This compound can be used not only in vitro, but also in vivo as a PET or SPECT ligand. There appears to be much interest in this substance and we expect that it will become a fairly heavily utilized ligand. We continue to identify novel analogs. Dr. Ivy Carroll, the chemist supervising the synthetic work, continues to be enthusiastic about this project.