SYNTHESIS AND BIOACTIVITY OF POTENTIAL DELTA ANTAGONISTS

该提案的长期目标是综合和发展 高度选择性的Delta1和Delta2选择性阿片类拮抗剂。这些 代理商将在确定Delta的潜在角色方面产生影响- 阿片受体在病理生理状态和治疗中的作用 某些疾病的症状。要研究的化合物将被设计成 莫菲南体系的C-6、C-7位附近的变异。一个 已知β-选择性阿片类药物关键原子间距离的比较 对抗者建议，一组三个距离在 确定选择性。结构活性关系还表明 C-6、C-7区域中芳香族部分的存在是 很重要。为了验证这一假设，纳曲酮和纳曲酮的结构 纳洛酮将通过一些杂芳烃系统进行修饰，例如 不同的氮唑与它们融合，特别是在C-6和C-7上。这是有计划的 合成了一系列3，14β-二羟基-4，5α-环氧基-6，7- 要发送到的didehydro-17-(cyclopropylmethyl-orallyl-)morphinians 连接在C6和C-7上：(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(取代在吡啶环中)。此外，还有一些 7-(杂芳基)-和7-(α-和β-杂芳甲基)-纳曲酮 将制备纳洛酮，其中杂芳基最初 将是2-呋喃、2-吡咯、3-吲哚、2-、3-和4-吡啶。 组件将包括在u、Delta1、Delta2的活动中 和k-阿片受体通过测定其IC50和k(I)值 高选择性~3H-配体~3H-DAMGO(MU)、~3H-U-69593的置换 (K)，~3H-DPDPE(Delta1)和~3H-DSTLE(Delta2)在100 nm DAMGO存在下 以抑制MU站点。)如果出现以下情况，则认为选择性较高 任意配基上的k(I)与三角洲位置上的k(I)之比很高。鼠标血管 还将使用输精管(MVD)和豚鼠回肠(GPI)制剂 以评价合成化合物的选择性。的IC50值 各种激动剂(Mu、Delta、K)将在存在和 不存在已知浓度的测试化合物。这将是 然后测定了IC50比值、k(E)值和它们的 比率(Mu/Delta和k/Delta)以及分析和解释将 如上所述。最后，体内活性(止痛剂)将 在MU、Delta和K激动剂不存在和存在的情况下测定 测试化合物。脑室内和外周的影响 (皮下)给药测试化合物的能力 拮抗µ、β、K-激动剂的活性以评估 该化合物的疏水性质(它是否可以通过血液- 脑屏障)将被确定。这些研究可能会导致 高选择性β受体拮抗剂的体外和体内研究进展 活体活动。

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.