BIVALENT LIGANDS AS OPIOID RECEPTOR PROBES

这项研究的长期广泛目标是发展可逆的 对特定阿片受体类型具有选择性的拮抗剂 子类型。理想情况下，这些配体对代谢应该相对稳定。 失活，能够穿透血脑屏障，并具有很高的 目标站点的亲和力和效力。我们将使用这样的配体 工具，以分类产生的生理和药理作用 内源性或外源性阿片类药物。 我们将合成两类二价配体。头等舱 包含两个纳曲酮衍生的药效团，第二类是 以单一拮抗剂药效团为特征的(“信息”)加入 至指定为地址(A)的非药效团识别单元 赋予亚型选择性的配体的一部分)。的一项关键功能 这两个二价配体类别预计将在 赋予选择性是刚性间隔物的存在 识别单元。 在二聚二价配体中，刚性的几何构型和长度 间隔物将不同，以调查之间的关系 严格控制的药效团和阿片类拮抗剂的定位 选择性。这些结构选择性研究旨在 为我们提供了对这些配体与 不同的阿片受体类型。当这样的研究表明 同时占用单个站点的“消息”和“地址”子站点 阿片受体通过配基参与，是阿片受体的一个药效团。 二聚体将被赋予的关键地址部分所取代 选择性。这种配体代表第二类二价配体 如上所述。总共提出了43个目标化合物。 通过四条不同的路线进行合成。 所有目标化合物都将在三种平滑肌制剂中进行测试 在阿片受体结合试验中。将对选择性配体进行评估 进一步在小鼠身上使用两种不同的抗伤害性试验。 将对kappa拮抗剂Nor-BNI及其 同系物，以确定它们是作用于单个还是多个 Kappa阿片受体的种群。

The long-term broad objectives of this research are to develop reversible antagonists that are selective for specific opioid receptor types and subtypes. Ideally, these ligands should be relatively stable to metabolic inactivation, be able to penetrate the blood-brain barrier, and have high affinity and potency for the target sites. We will employ such ligands as tools to sort out the physiologic and pharmacologic effects produced by endogenous or exogenous opioids. Two classes of bivalent ligands will be synthesized. The first class contains two naltrexone-derived pharmacophores, the second class is characterized by a single antagonist pharmacophore (the "message") joined to a non-pharmacophore recognition unit designated as the "address" (a portion of the ligand that confers subtype selectivity). A key feature of both bivalent ligand classes that is expected to play an important role in conferring selectivity is the presence of rigid spacers that connect the recognition units. In the dimeric bivalent ligands, the geometry and length of the rigid spacers will be varied in order to investigate the relationship between the orientation of the rigidly held pharmacophores and opioid antagonist selectivity. These structure-selectivity studies have been designed to provide us with insight into the mode of interaction of such ligands with different opioid receptor types. When such studies suggest that simultaneous occupation of the "message" and "address" subsites of a single opioid receptor by a ligand is involved, one of the phamacophores of the dimer will be replaced with the key address moieties that confer selectivity. Such ligands represent the second class of bivalent ligands mentioned above. A total number of 43 target compounds have been proposed for synthesis by four different routes. All target compounds will be tested in three smooth muscle preparations and in the opioid receptor binding assay. Selective ligands will be evaluated further in mice using two different antinociceptive assays. Further studies will be conducted on the kappa antagonist nor-BNI and its congeners to determine if they are acting on a single or multiple populations of kappa opioid receptors.