Diterpines as Selective Kappa Opioid Receptor Agonists

描述（由申请方提供）：鼠尾草素A -致幻鼠尾草的活性成分-沿着鼠尾草，代表了美国和其他地方的新兴滥用药物。鼠尾草素A和鼠尾草提取物在人类中诱导强烈和短暂的幻觉体验，这与经典致幻剂LSD、裸盖菇素和美斯卡灵不同。在2002年，我的实验室发现鼠尾草素A有效且特异性地靶向？阿片受体（KOR）（Roth等，PNAS 2002）;这些发现已被广泛复制。尽管人们对鼠尾草素A的作用非常感兴趣，但我们仍然没有完全理解其在KOR的精致效力和选择性的分子和原子机制。这些研究的目的是发现鼠尾草素A如何结合并激活KOR。为了实现这些目标，我们将进行两个具体的目标：（1）阐明结构特征？阿片受体的salvinorin A的行动所必需的高通量分子生物学和（2）阐明的结构特征？阿片受体负责salvinorin A的行动，通过直接的生物化学方法。这些研究将阐明这种滥用药物如何在原子水平上发挥作用。这些研究的意义如下：概念：鼠尾草素A是一种新出现的滥用药物，对人类感知有深远影响。鼠尾草素A通过有效和选择性激活？阿片受体了解鼠尾草素A如何实现其对KOR的显著选择性和效力是阐明鼠尾草素A作用机制的重要第一步。技术：我们将利用我们发明的新颖且非常稳健的基于酵母的技术（Armbruster等人，2007 a）以鉴定鼠尾草素A结合并活化KOR的分子和原子机制。我们还将采用新合成的PM亲和性和不可逆的鼠尾草素A类似物来鉴定KOR上负责结合的残基。据我们所知，这些将是阿片受体领域的第一项研究，以生物化学方式识别结合口袋中的残基。 公共卫生相关性： 鼠尾草及其活性成分salvinorin A代表了美国新兴的滥用药物。这些研究可能会导致药物滥用的新疗法。

DESCRIPTION (provided by applicant): Salvinorin A - the active ingredient of the hallucinogenic sage Salvia divinorum - along with Salvia divinorum represent emerging drugs of abuse in the US and elsewhere. Salvinorin A and extracts of Salvia divinorum induce an intense and short-lived hallucinatory experience in humans unlike that of the classical hallucinogens LSD, psilocybin and mescaline. In 2002, my lab discovered that salvinorin A potently and specifically targets ?-opioid receptors (KOR) (Roth et al., PNAS 2002); these findings have been widely replicated. Despite intensive interest in the actions of salvinorin A, we still do not fully understand the molecular and atomic mechanisms responsible for its exquisite potency and selectivity at KOR. The goal of these studies is to discover how salvinorin A binds to and activates KOR. To accomplish these goals we will conduct two specific aims: (1) elucidate the structural features of ?-opioid receptors essential for salvinorin A's actions using high-throughput molecular biology and (2) elucidate the structural features of ?-opioid receptors responsible for salvinorin A's actions via direct biochemical approaches. These studies will clarify how this drug of abuse exerts its actions at the atomic level. These studies are significant as follows: Conceptual: Salvinorin A is an emerging drug of abuse which has profound effects on human perception. Salvinorin A exerts these actions via potent and selective activation of ?-opioid receptors. Understanding how salvinorin A achieves its remarkable selectivity and potency for KORs is an essential first step toward elucidating the mechanism of action of salvinorin A. Technical: We will utilize novel and extraordinarily robust yeast-based technologies we have invented (Armbruster et al., 2007a) to identify the molecular and atomic mechanisms by which salvinorin A binds to and activates KORs. We will also employ newly synthesized pM-affinity and irreversible salvinorin A analogues to identify residues on KOR responsible for binding. To our knowledge, these will be the first studies in the opioid receptor field to biochemically identify residues in the binding pocket. PUBLIC HEALTH RELEVANCE: Salvia divinorum and its active ingredient salvinorin A represent emerging drugs of abuse in the US. These studies could lead to novel treatments for drug abuse.