SYNTHESIS AND BIOACTIVITY OF POTENTIAL DELTA ANTAGONISTS

该提案的长期目标是综合和发展 高选择性δ 1和δ 2选择性阿片拮抗剂。 这些 代理人将在确定三角洲的潜在作用的影响- 阿片受体在病理生理状态以及治疗中的作用 某些疾病。 要研究的化合物将被设计为 mophinan系统的C-6，C-7位置周围的变化。 一 已知δ-选择性阿片类药物的关键原子间距离的比较 拮抗剂表明，一组三个距离是重要的， 确定选择性。 结构活性关系也表明 C-6、C-7区域中芳香族部分的存在是 重要. 为了验证这一假设，研究了纳洛酮和 纳洛酮将通过具有一些杂芳族系统，如 各种唑与它们稠合，特别是在C-6和C-7。 计划 合成了大量的3，14 β-二羟基-4，5 α-环氧-6，7-二羟基苯甲酸酯， 二异丙基-17-（环丙基甲基-或烯丙基-）吗啡啉， 在C6和C-7处连接的：（2 ′-烷基-或2 ′-芳基）-4 ′，5 ′-咪唑，（2-烷基- 或2 ′-芳基）-4 ′，5 ′-噻唑和8 ′，7 ′-咪唑[1，2- a]吡啶（在吡啶环中被取代）。 此外，一些 7-（亚杂芳基）-和7-（α-和β-杂芳基甲基）-纳洛酮 和纳洛酮，其中杂芳基最初 可以是2-呋喃基、2-吡咯基、3-吲哚基、2-、3-和4-吡啶基。 将纳入组件的mu、delta 1、delta 2活性 和k-阿片受体的IC 50和k（i）值， 高选择性3 H-配体的置换，3 H-DAMGO（mu），3 H-U-69593 (k)在100 nM DAMGO存在下，3 H-DPDPE（delta 1）和3 H-DSTLE（delta 2） 以抑制mu站点。） 选择性将被视为高，如果 任何配体处的k（i）与δ位点处的k（i）的比率都很高。 鼠输精管 还将使用输精管（MVD）和豚鼠回肠（GPI）制备物 以评估合成化合物的选择性。 的ic 50值 各种激动剂（μ，δ，K）将在存在和 不存在已知浓度的测试化合物。 这将是 随后测定IC 50比率、k（e）值及其 比率（mu/delta和k/delta），分析和解释将 就像上面做的。 最后，体内活性（镇痛剂）将是 在不存在和存在以下物质的情况下测定μ、δ和k激动剂 测试化合物。 脑室内和外周的影响 （皮下）施用测试化合物以测定其 拮抗μ的活性，δ，k -激动剂以评估 化合物的疏水性质（它是否可以穿过血液- 脑屏障）将被确定。 这些研究可能会导致 体外和体内高选择性δ-拮抗剂的开发 体内活性

The long-term objectives of the proposal are to synthesize and develop highly selective delta1- and delta2-selective opiate antagonists. These agents will have implications in determining the potential role of delta- opiate receptors in pathophysiological states as well as in the treatment of certain disorders. The compounds to be studied will be designed with variation around the C-6, C-7 positions of the mophinan system. A comparison of key interatomic distances of known delta-selective opiate antagonists suggests that a set of three distances are important in determining selectivity. Structure activity relationships also suggest that the presence of an aromatic moiety in the C-6, C-7 region is important. To test this hypothesis, the structures of naltrexone and naloxone will be modified by having some heteroaromatic systems, such as various azoles fused to them, specifically at C-6 and C-7. It is planned to synthesize a number of 3,14Beta-dihydroxy-4,5alpha-epoxy-6,7- didehydro-17-(cyclopropylmethyl-orallyl-)morphinians to which are attached at C6 and C-7:(2'-alkyl-or2'-aryl)-4',5'-imidazoles,(2-alkyl- or2'-aryl)-4',5'-thiazoles, and 8',7'-imidazol[1,2- a]pyridines(substituted in the pyridine ring). In addition, a number of 7-(heteroarylidene)-and 7-(alpha- and Beta-heteroarylmethyl)-naltrexones and nalozones will be prepared, where the heteroaryl groups initially will be 2-furyl, 2-pyrryl, 3-indolyl, 2-,3-, and 4-pyridyl. The components will be included for their activity at mu, delta1, delta2 and k-opiate receptors by determining the IC50 and k(i) values for their displacement of highly selective 3H-ligands, 3H-DAMGO (mu), 3H-U-69593 (k), 3H-DPDPE (delta1) and 3H-DSTLE (delta2) in presence of 100 nM DAMGO to suppress mu sites.) The selectivity will be considered high if the ratio of k(i) at any ligand to the k(i) at delta site is high. Mouse vas deferens (MVD) and guinea-pig ileum (GPI) preparations will also be used to assess the selectivity of the synthesized compounds. IC50 values for various agonists (mu, delta, K) will be determined in the presence and absence of a known concentration of the test compound. This will be followed by the determination of the IC50 ratios, k(e) values and their ratios (mu/delta and k/delta) and the analysis and interpretation will be made as above. Finally, in vivo activity (analgesic) will be determined for mu, delta, and k agonists in the absence and presence of the test compound. The effects of intracerebroventricular and peripheral (subcutaneously) administration of the test compound for its ability to antagonize the activity of mu., delta, k - agonists in order to assess the hydrophobic nature of the compound (whether it can cross the blood- brain barrier) will be determined. These studies may lead to the development of highly selective delta-antagonists for in vitro and in vivo activity.