SELECTIVE OPIOID ANTAGONISTS

这个项目的长期目标是创造高度选择性的 非肽类阿片受体拮抗剂的药理和生化研究 调查：a)梳理阿片受体类型和亚型，b)调查 内源性和外源性阿片受体介导的作用 配体，以及c)发现这种阿片类药物的潜在临床应用 对抗者。设计原理涉及对纳曲酮的修改，包括 A Key“Address：赋予阿片受体类型选择性的要素 或者说亚型。地址部分将附在纳曲酮上 通过间隔物具有不同柔韧性和 方向，以努力评估移动性和 地址基团的构象和配体的选择性。这些研究 将包括三角洲和kappa选择性拮抗剂的配体。 将进行计算机辅助分子建模，以努力 确定选择性非肽中的关键元素是否 占据与选择性阿片肽相同的构象空间。一个 新型激动剂-拮抗剂混合配体的设计方法将是 作为设计强效止痛药的一种方法。三个系列 的非平衡拮抗剂将被合成并评估 Delta型和Kappa受体亚型的选择性。这些配体是以 在纳曲哚(NTI)或其苯并呋喃类似物(NTB)中。这个 选择Delta的拮抗剂将含有亲电基团 吲哚、苯并呋喃部分或N-苄基取代基上。卡帕- 选择性非平衡拮抗剂含有一个附加的基本部分 通过亚甲基连接到吲哚系统的5‘位， 连接在N-苄基取代基上的亲电基团。协作性 将与NTI和NTB进行研究，以研究他们的能力 抑制酒精和可卡因的摄取。

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.