TREATMENT DRUGS AND MOLECULAR PROBES FOR NARCOTIC ABUSE

对4-苯胺基哌啶类镇痛药的研究产生了两种 临床上有用的药物和分子探针，用于研究鸦片制剂 受体的本申请的目标是开发改进的实施方案。 基于顺式-β-羟基-3-甲基芬太尼的化合物， 芬太尼和顺式-3-甲基芬太尼的高效类似物。 具体目的如下：a）分离以下化合物的立体异构体： 顺式-β-羟基-3-甲基芬太尼，并确定绝对值 B）合成最有效的化合物的类似物， 顺式-β-羟基-3-甲基芬太尼，其中系统结构 在分子的不同部分进行变化，c）以获得 体内生物学试验数据并进行体外配体结合 阿片受体的六种亚型（μ，δ（Cx，） δ（ncx）、κ（l）、κ（2a）、κ（2b），以及 d）对制备的所有化合物进行详细的NMR分析。的 结构变化集中在β-羟基-β-苯乙基部分， 分子，顺式-3-甲基取代基， 哌啶环和分子的丙酰苯胺部分。包括 在结构变化中的特征可以减少或 消除呼吸抑制作用，同时保持止痛 力量 从拟议的研究中获得的知识将提供更广泛的 了解4-苯胺基哌啶类镇痛药。这样的 理解可能转化为开发有效的止痛药 没有不良副作用如呼吸抑制的药物 和/或开发新的治疗药物和分子探针 因为滥用毒品

Studies on the 4-anilinopiperidine class of analgesics have produced both clinically useful drugs and molecular probes for studying the opiate receptor. The goal of the present application is to develop improved compounds based on cis-beta-hydroxy-3-methylfentanyl, a relatively new and highly potent analog of fentanyl and cis-3-methylfentanyl. The specific aims are as follows: a) to separate the stereoisomers of cis-beta-hydroxy-3-methylfentanyl and determine the absolute stereochemistries of the most potent ones, b) to synthesize analogs of cis-beta-hydroxy-3-methylfentanyl in which systematic structural variations are made in different parts of the molecule, c) to obtain in vivo biological test data and to carry out in vitro ligand binding studies on six different opiate receptor subtypes (mu, delta(cx,) delta(ncx), kappa(l), kappa(2a), kappa(2b) on all compounds prepared, and d) to carry our detailed NMR analyses on all compounds prepared. The structural variations focus on the beta-hydroxy-beta-phenethyl portion of the molecule, the cis-3-methyl substituent, the 4-position of the piperidine ring, and the propionanilide portion of the molecule. Included among the structural variations are features which may reduce or eliminate respiratory depressant effects while maintaining analgesic potency. The knowledge derived from the proposed study will provide a broader understanding of the 4-anilinopiperidine class of analgesics. Such an understanding may translate into the development of potent analgesic agents devoid of adverse side effects such as respiratory depression and/or into the development of new treatment drugs and molecular probes for narcotic abuse.