Diterpines as Selective Kappa Opioid Receptor Agonists

描述（由申请人提供）： 重要性：鼠尾草素A是一种天然存在的新克拉烷二萜品，并且是“神奇薄荷”致幻植物鼠尾草的主要活性成分，是一种有效的和选择性的k-阿片受体激动剂（Roth et al.，Proc Natl Acad Sci USA，2002）。因此，鼠尾草和鼠尾草素A代表一类新的滥用药物（Sheffler和Roth，Trends Pharmacol Sci，出版中），其选择性靶向κ-阿片受体。地萜品是一种选择性肽受体激动剂的发现是独特的和前所未有的。因此，阐明鼠尾草素A对k-阿片受体的作用的结构特征将阐明肽药物设计的新方法。对鼠尾草素A与k-阿片受体相互作用的研究也可以提供一个案例研究，代表一种创新策略，用于设计具有极高选择性的药物。因此，非胺配体，如鼠尾草素A，具有几乎绝对选择性的潜力。为了实现这一总体目标，我们将测试以下两个假设和5个具体目标：假设#1：鼠尾草素A以独特的方式与k-阿片受体相互作用。具体目标1：通过定点诱变和分子建模的组合确定结合鼠尾草素A所必需的k-阿片受体的结构特征。具体目标2：通过定点诱变和分子建模方法的组合，确定KOR处鼠尾草素A激动剂作用所必需的k-阿片受体的结构特征。具体目标#3：比较鼠尾草素A与所选生物碱激动剂对KOR的结合和活化模式。假设#2：鼠尾草素A的2-甲氧基羰基位置对于k-阿片受体的结合和活化至关重要。具体目标4：比较一系列天然存在的和合成的2-取代Saivinorin A衍生物的结合和功能特性。这些研究可能会阐明鼠尾草素A和相关滥用药物如何在分子和细胞水平上介导其作用，并将导致治疗与鼠尾草素A滥用相关的副作用。

DESCRIPTION (provided by applicant): Significance: Salvinorin A, a naturally occurring neoclaridane diterpine and the main active ingredient of the 'magic mint' hallucinogenic plant Salvia divinorum, is a potent and selective k-opioid receptor agonist (Roth et al., Proc Natl Acad Sci USA, 2002). Salvia divinorum and Salvinorin A thus represent a novel class of abused drugs (Sheffler and Roth, Trends Pharmacol Sci, in press) which selectively target the kappa-opioid receptor. The discovery that a diterpine is a selective peptide receptor agonist is unique and unprecedented. Therefore, the elucidation of the structural features responsible for Salvinorin A's actions at k-opioid receptors will illuminate novel approaches for peptide drug design. Investigation of the interaction of Salvinorin A with the k-opioid receptor may also provide a case study representing an innovative strategy for the design of drugs with exceptionally high selectivity. Thus, non-amine ligands, such as salvinorin A, have a potential for nearly absolute selectivity. To accomplish this overall goal we will test the following two hypotheses and 5 specific aims: Hypothesis #1: Salvinorin A interacts with the k-opioid receptor in a unique manner. Specific aim #1: To determine the structural features of the k-opioid receptor essential for binding Salvinorin A via a combination of site-directed mutagenesis and molecular modeling. Specific aim #2: To determine the structural features of the k-opioid receptor essential for the agonist actions of Salvinorin A at the KOR via a combination of site-directed mutagenesis and molecular modeling approaches. Specific aim #3: To compare the mode of binding and activation of the KOR by Salvinorin A with selected alkaloid agonists. Hypothesis #2: The 2-methoxycarbonyl position of Salvinorin A is essential for binding to and activation of the k-opioid receptor. Specific aim #4: To compare the binding and functional properties of a series of naturally occurring and synthetic 2-substituted Saivinorin A derivatives. These studies are likely to clarify how Salvinorin A and related drugs of abuse mediate their actions at the molecular and cellular levels and will lead to treatments for the side-effects related to Salvinorin A abuse.