AMINO ACID CONJUGATES OF OPIOID LIGANDS

该项目的广泛的长期目标是开发有效的， 选择性阿片拮抗剂和具有非常有限的 外周神经系统（CNS）的通路 局这类配体的应用将包括药理学 工具来研究的周边行动的二倍体没有 由中枢介导效应引起的应用。这样的配体具有 许多潜在的研究应用，包括它们作为工具的用途， 研究免疫调节，内分泌，胃肠道， 阿片类药物对肾脏和心血管的影响。 在本申请中，我们提出合成五个系列的阿片类化合物， 激动剂和拮抗剂，其含有衍生自 个氨基酸设计了目标化合物中的可电离基团 从而极大地阻碍了外周给药后进入CNS。在 为了赋予受体选择性，靶点中的药效团 化合物将衍生自已建立的非肽配体， 对μ、δ和κ阿片样物质已知药理学选择性 受体。 目标化合物首先将在豚鼠回肠中进行测试 纵肌和小鼠输精管准备， 评估其药理学选择性和效力，然后在 受体结合分析具有高选择性的目标化合物 和效力将在冰中的抗伤害性测定中测试， 通过三种不同途径给药（i. c. v.，i.v.和p.o.）。的 这些配体的选择性将在这些体内研究中进行评价 并建立外周-CNS效价比。 申请成为协作诊断中心， 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，扩展谱系，以及 美国爱斯基摩地理隔离分离精神分裂症已经 已识别并将被确认。一个亚组将接受诊断 在精神病理学的几个领域的评估，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）和精神药理学评价。 最终，将这些生物行为评估与 结果可允许鉴定内表型， 同质亚型的表征，表观遗传学的澄清 精神分裂症发病前病理生理学的认识

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