SELECTIVE SIGMA LIGANDS: DESIGN SYNTHESIS & EVALUATION

对西格玛药理学的了解相对较少，除了药物 与西格玛网站有明显的亲和力，要么会产生精神分裂症- 如精神病症状或减轻/减弱这种影响。论 根据这些发现，有人认为西格玛选择性 代理人(拮抗者)可能代表了一种新的机械性的 没有许多不良副作用的抗精神病药 与经典的神经镇静剂有关。西格玛-阿片类药物，各种 经典的抗精神病药物，如氟哌啶醇，和某些其他药物结合 在西格玛位点，但缺乏高亲和力和/或选择性。到目前为止，没有 高亲和力的Sigma选择剂已有报道。事实上，几乎没有 已以结构-活性关系(SAR)的方式发表 Sigma激动剂和Sigma激动剂的结构要求 对抗者是未知的。此外，西格玛的一个功能模型 激活似乎是由于缺乏高亲和力的Sigma选择性 激动剂。事实上，目前的研究似乎是由非 目前可用的选择性药物。因此，有必要 既用于开发高亲和力的Sigma选择性激动剂，也用于开发 对抗者。 拟议的调查，其目标是开发西格玛选择性 并确定各种结构特征如何影响亲和力， 内在的活性和选择性是第一个系统性的 涉及此类制剂的合理设计的研究。我们已经确定了 我们认为这是西格玛阿片类药物的主要药效基团。 这种药效团的结构修饰(即PAP)已经 导致几种药物结合在西格玛位点上，具有非常高的 亲和力。此外，与西格玛-阿片剂不同，PAP类似物几乎不显示 对五氯酚结合部位没有亲和力，与氟哌啶醇不同，它们 对多巴胺部位表现出低亲和力。模特研究揭示了 预期与西格玛位点结合的其他类型的化合物 与PAP类似物的亲和力相似或甚至更高。我们有 使用热力学外方法设计的新试剂，我们 建议使用体外放射性配基初步合成和评估 结合和药物识别技术(以大鼠为对象)。这个 结合研究将提供Sigma亲和力的测量(激动剂与 对抗作用)。随后的药物歧视研究将采用 我们的一种新的，更有选择性的西格玛激动剂作为训练药物。 总体而言，我们的调查将允许确定 分子特征对于亲和力、内在活性和 选择性。此外，根据我们的初步结果，我们 还建议制备新的放射性配体，这些配体应该对 Sigma受体/结合部位的进一步表征。

Relatively little is known about sigma pharmacology except that agents with appreciable affinity for sigma sites either produce schizophrenic- like psychotic symptoms or alleviate/attenuate such effects. On the basis of these findings, it has been suggested that sigma-selective agents (antagonists) might represent a new mechanistic class of neuroleptic agents that lack many of the undesirable side effects associated with the classical neuroleptics. Sigma-opiates, various classical neuroleptics such as haloperidol, and certain other agents bind at sigma sites, but lack high affinity and/or selectivity. To date, no high-affinity sigma-selective agents have been reported. In fact, little has been published in the way of structure-activity relationships (SAR) for sigma agents, and structural requirements for sigma agonists and antagonists are unknown. Furthermore, the one functional model of sigma activation appears to suffer from a lack of high affinity sigma-selective agonists. Indeed, current studies are seemingly dictated by the non- selective agents that are presently available. Thus, there is a need both for the development of high-affinity sigma-selective agonists and antagonists. The proposed investigation, whose goals are to develop sigma-selective agents and to determine how various structural features affect affinity, intrinsic activity, and selectivity, represents the first systematic study involving the rational design of such agents. We have identified what we believe is the primary pharmacophore of the sigma-opiates. Structural modification of this pharmacophore (i.e. PAP) has already resulted in several agents that bind at sigma sites with very high affinity. Furthermore, unlike sigma-opiates, PAP analogs display little to no affinity for PCP binding sites, and unlike haloperidol, they display low affinity for dopamine sites. Modeling studies have revealed other types of compounds that are anticipated to bind at sigma sites with similar or an even higher affinity than the PAP analogs. We have designed, using an extrathermodynamic approach, new agents that we propose to synthesize and evaluate using, initially, in vitro radioligand binding and drug discrimination techniques (with rats as subjects). The binding studies will provide a measure of sigma affinity (agonist vs antagonist action). Subsequent drug discrimination studies will employ one of our novel, more selective sigma agonists as a training drug. Overall, then, our investigations will permit the determination of what molecular features are important for affinity, intrinsic activity, and selectivity. In addition, on the basis of our preliminary results, we also propose to prepare new radioligands that should be useful for the further characterization of sigma receptor/binding sites.