SELECTIVE OPIOID ANTAGONISTS

该项目的长期目标是创造高选择性的 作为药理学和生物化学的非肽类阿片受体拮抗剂 探针：a）分类阿片受体类型和亚型，B）研究 阿片受体介导的内源性和外源性阿片作用 配体，和c）揭示这种阿片样物质的潜在临床应用 对手。 设计原理涉及纳洛酮的修饰， 关键“地址：赋予阿片受体类型选择性的元素 或亚型。 地址部分将连接到纳洛酮 通过具有不同柔韧性的间隔物， 方向，以评估流动性和 地址部分的构象和配体选择性。 这些研究 将包括δ-和κ-选择性拮抗剂的配体。 计算机辅助分子建模将努力进行， 确定选择性非肽中的关键元件是否 占据与选择性阿片肽相同的构象空间。 一个 设计新型混合激动剂-拮抗剂配体的方法将是 作为设计强效镇痛药的一种方法。 三大系列 非平衡拮抗剂将被合成和评估， 对δ和κ受体亚型的选择性。 这些配体是基于 纳曲吲哚（NTI）或其苯并呋喃类似物（NTB）。 的 δ-选择性拮抗剂将含有亲电子基团， 吲哚、苯并呋喃部分或在N-苄基取代基上。 卡帕- 选择性非平衡拮抗剂含有连接的碱性部分 通过亚甲基连接到吲哚系统的5'位， 亲电子基团连接到N-苄基取代基。 协同 将与NTI和NTB进行研究，以研究它们的能力， 抑制乙醇和可卡因摄取。

The long term objective of this project is to create highly selective nonpeptide opioid receptor antagonists as pharmacological and biochemical probes to: a) sort out opioid receptor types and subtypes, b) investigate opioid receptor-mediated actions of endogenous and exogenous opioid ligands, and c) uncover potential clinical applications of such opioid antagonists. The design rationale involves modification of naltrexone with a key "address: element to confer selectivity for an opioid receptor type or subtype. The address moiety will be attached to the naltrexone morphinan system through spacers that have different flexibilities and orientations in an effort to evaluate the relationship of the mobility and conformation of the address moiety and ligand selectivity. These studies will include ligands that are delta- and kappa-selective antagonists. Computer-aided molecular modeling will be carried out in an effort to determine whether or not the key elements in the selective nonpeptides occupy the same conformational space as selective opioid peptides. An approach to the design of novel mixed agonist-antagonist ligands will be undertaken as an approach to the design of potent analgesics. Three series of nonequilibrium antagonists will be synthesized and evaluated for selectivity at delta and kappa receptor subtypes. These ligands are based either on naltrindole (NTI) or in its benzofuran analogue (NTB). The delta-selective antagonists will contain electrophilic groups on the indole, benzofuran moiety, or on a N-benzyl substituent. The kappa- selective nonequilibrium antagonists contain a basic moiety attached through a methylene group to the 5' position of the indole system, with electrophilic groups attached to an N-benzyl substituent. Collaborative studies will be carried out with NTI and NTB to study their ability to suppress ethanol and cocaine uptake.