SUBTYPE SELECTIVE LIGANDS FOR OPIATE RECEPTORS

介导了多种生理和药理作用 通过中枢神经系统的鸦片受体。 设计在三者之间 已确定的阿片受体类别（μ、δ、κ）最近 研究工作集中在受体的δ亚型上。 大量证据表明δ受体参与了 在介导脊髓和脊髓上抗伤害感受、胃肠道 过境和调节发展的容忍和依赖， 阿片类药物和其他滥用药物，如可卡因。 显著 阿片δ受体药理学的发展是最近的 δ受体亚型的生物化学和药理学描绘 称为delta/1和delta/2亚型或delta/ncx 和δ/Cx受体。 最近的研究表明， 在这些δ受体亚型中，进一步的研究最终可能 导致它们被分类为另外亚型。 识别 阿片δ受体亚型的研究是一个令人兴奋的新进展， 为开发亚型选择性药物提供了机会， 作为新型镇痛剂的治疗应用（没有胃肠道， 呼吸和药物依赖性副作用）和作为治疗药物用于 与毒品添加有关的问题。 高选择性激动剂和拮抗剂配体的研究进展 对于阿片δ受体的各种亚型， 重要性，因为需要稳定的和选择性的配体用作 药理学工具和选择性药物具有最小的副作用。 拟议工作的一个长期目标是发展稳定的 具有特异性激动剂或拮抗剂活性的非肽配体， 对这些不同δ受体亚型的选择性。 为了努力 实现这些目标，本文提出的是一个合作的努力， 药物设计、合成以及体外和体内评价， 组织和动物模型中。 一种方法，已被采用，在 设计新的配体是利用最近的观察δ 对某些吗啡喃衍生物的选择性作为 合理的结构操作，可能会赋予所需的功效， 对δ受体亚型的选择性。 综合与评价 所设想的吲哚并-、吡啶并-和嘧啶吗啡喃目标化合物 应该提供关于配体结合特性的新见解 阿片样物质δ受体亚型。 此外，拟议的研究 应有助于识别新的δ受体亚型选择性 可以潜在地用作镇痛剂和治疗剂的试剂 用于治疗耐受性和依赖性问题的药物 滥用药物。

A wide variety of physiological and pharmacological actions are mediated by the opiate receptors of the central nervous system. Among the three well established classes of opiate receptors (mu, delta, kappa) recent research efforts have focused attention on the delta subtype of receptors. A large body of evidence indicates that the delta receptors are involved in mediating spinal and supraspinal antinociception, gastrointestinal transit and in modulating the development of tolerance and dependence to opioid and other drugs of abuse such as cocaine. A significant development in the opioid delta receptor pharmacology is the recent biochemical and pharmacological delineation of subtypes of delta receptors which have been termed the delta/1 and delta/2 subtypes or the delta/ncx and delta/cx receptors. Recent studies suggest that heterogeneity exists among these subtypes of delta receptors and further studies may eventually lead to their classification into additional subtypes. The identification of subtypes of opioid delta receptors is an exciting new development which provides opportunities for development of subtype selective drugs for therapeutic applications as novel analgesics (devoid of gastrointestinal, respiratory and drug dependence side effects) and as treatment drugs for problems related to drug additions. The development of agonist and antagonist ligands with high selectivity for the various subtypes of opioid delta receptors is of primary importance since stable and selective ligands are needed for use as pharmacological tools and as selective drugs with minimal side effects. A long term objective of the proposed work is the development of stable nonpeptide ligands with specific agonist or antagonist activity and high selectivity for these various delta receptor subtypes. In an effort to achieve these goals, proposed herein is a collaborative effort involving drug design, synthesis and in vitro and in vivo evaluations in isolated tissues and in animal models. An approach that has been adopted in the design of novel ligands is to utilize the recent observations of delta selectivity for some of the morphinan derivatives as a starting point for rational structural manipulations that might impart desired efficacy and selectivity for the delta receptor subtypes. The synthesis and evaluation of the envisioned indolo-, pyrido- and pyrimidomorphinan target compounds should provide new insights regarding the ligand binding characteristics of the opioid delta receptor subtypes. Moreover, the proposed studies should aid in the identification of new delta receptor subtype selective agents that may potentially be useful as analgesics and as therapeutic agents for the treatment of tolerance and dependence problems associated with drugs of abuse.