AMINO ACID CONJUGATES OF OPIOID LIGANDS

该项目的广泛、长期目标是开发强有力的、 选择性阿片类拮抗剂和拮抗剂 在外围设备上访问中枢神经系统(CNS) 行政管理。这些配体的应用将是药理方面的。 研究无外源二倍体外周行为的工具 由集中调节效应引起的应用。这样的配体已经 许多潜在的研究应用，包括将其用作工具 研究免疫调节，内分泌，胃肠， 阿片类药物对肾脏和心血管的影响。 在这一应用中，我们建议合成五个系列的阿片类药物 含有源自以下的可电离基团的激动剂和拮抗剂 氨基酸。设计了目标化合物中的电离基团 在外周给药时极大地阻碍进入中枢神经系统。在……里面 为了赋予受体选择性，靶标中的药效载体 化合物将从已建立的非肽配体衍生而来 已知的Mu、Delta和Kappa阿片类药物的药理选择性 感受器。 目标化合物首先将在豚鼠回肠上进行测试 并在小鼠输精管纵行肌层内准备 评估它们的药理选择性和效力，然后在 受体结合试验。具有高选择性的目标化合物 效力将在冰中的抗伤害感受性试验中测试 通过三种不同的途径(I.C.V.、I.V.和P.O.)进行管理。这个 这些配体的选择性将在体内研究中进行评估。 并建立外周-中枢神经系统的效力比。 应用程序将成为一个协作诊断中心 精神病学联系研究(精神分裂症)。人口结构多样化 家庭，包括受影响的核心家庭，扩展的家系，以及 美国爱斯基摩人的地理隔离精神分裂症 已被确认并将被确定。一个小组将接受诊断 在精神病理学的几个领域进行评估，以及 心理测量学、神经心理学、心理生理学、神经放射学 (结构和功能)和精神药理学评估。 最终，将这些生物行为评估与关联 结果可以允许识别内表型， 同质亚型的表征，表观遗传学的澄清 精神分裂症病前病理生理的影响因素及再认识

The broad, long-term objectives of this project are to develop potent, selective opioid antagonists and antagonists that have very limited access to the central nervous system (CNS) upon peripheral administration. The applications of such ligands will e as pharmacologic tools to study the peripheral actions of oploids without the applications arising from centrally mediated effects. Such ligands have many potential research applications, including their use as tools for investigating the immunodulatory, endocrinological, gastrointestinal, renal, and cardiovascular effects of opiods. In this application we propose to synthesize five series of opioid agonists and antagonists which contain ionizable groups derived from amino acids. The ionizable groups in the target compounds are designed to greatly impede access into the CNS upon peripheral administration. In order to confer receptor selectivity, the pharamacophores in the target compounds will be derived from established, nonpeptide ligands with known pharmacologic selectivity for mu, delta, and kappa opioid receptors. The target compounds first will be tested in guinea pig ileal longitudinal muscle and in the mouse vas deferens preparation to evaluate their pharmacologic selectivity and potencies, and then in the receptor binding assay. Target compounds that possess high selectivity and potency will be tested in antinociceptive assays in ice after administration by three different routes (i.c.v., i.v.', and p.o.). The selectivity of these ligands will be evaluated in these in vivo studies and peripheral-CNS potency ratio will be established. Application is made to become a collaborating Diagnostic Center for Psychiatric Linkage Studies (Schizophrenia). Demographically diverse families including affected nuclear families, extended pedigrees, and an American eskimo geographic isolate segregating schizophrenia have been identified and will be ascertained. A subgroup will undergo diagnostic assessment in several domains of psychopathology, as well as psychometric, neuropsychologic, psychophysiologic, neuroradiologic (structural and functional), and psychopharmacologic evaluations. Ultimately, combining these biobehavioral assessments with linkage results may allow for the identification of endophenotypes, characterization of homogenous subtypes, clarification of epigenetic factors, and recognition of premorbid pathophysiology in schizophrenia