BIVALENT LIGANDS AS OPIOID RECEPTOR PROBES

这项研究的长期广泛目标是开发可逆的 对特定阿片受体类型具有选择性的拮抗剂， 亚型理想地，这些配体应该对代谢相对稳定。 失活，能够穿透血脑屏障，并具有高 对靶位点的亲和力和效力。我们将使用这样的配体， 工具来整理产生的生理和药理作用， 内源性或外源性阿片样物质。 将合成两类二价配体。头等舱 含有两个纳洛酮衍生的药效团，第二类是 其特征在于单个拮抗剂药效团（“信息”） 到指定为“地址”的非药效团识别单元（a 赋予亚型选择性的配体部分）。的一个关键特征 这两种二价配体类别，预期在 赋予选择性的是刚性间隔物的存在， 识别单位。 在二聚体二价配体中，刚性配体的几何形状和长度是可变的。 间隔物将被改变，以研究 刚性固定的药效团和阿片类拮抗剂的方向 选择性。这些结构选择性研究旨在 为我们提供了深入了解这种配体与 不同的阿片受体类型当这些研究表明， 同时占用“消息”和“地址”子网站的单一 阿片受体的配体参与，其中一个phamacophores的 二聚体将被关键地址部分取代， 选择性。这样的配体代表第二类二价配体 上面提到的。共提出了43个目标化合物 通过四种不同的途径合成。 所有目标化合物将在三种平滑肌制备物中进行测试， 在阿片受体结合试验中。将对选择性配体进行评价 进一步在小鼠中使用两种不同的抗伤害感受测定。 将对κ拮抗剂nor-BNI及其抑制剂进行进一步的研究。 以确定它们是作用于单一或多个 kappa阿片受体的数量。

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.