Differentiation of δ, μ, and κ opioid receptor agonists based on pharmacophore development and computed physicochemical properties
Differentiation of δ, μ, and κ opioid receptor agonists based on pharmacophore development and computed physicochemical properties
复制标题
DOI：
10.1023/a:1011187320095
复制
发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Loew, GH
中科院分区：
文献类型：
--
作者：
Filizola, M;Villar, HO;Loew, GH
与阿片受体类型 δ、mu 和 kappa 具有显着亲和力结合的化合物，对这三种受体具有不同的激活和抑制组合，可能是有前途的行为选择性药物。根据这一假设，鉴定了三组不同的阿片受体激动剂所共有的化学部分，这些激动剂对三种受体类型 δ、mu 或 kappa 中的每一种都具有显着的亲和力。使用距离分析方法，针对选定的 delta、mu 或 kappa 阿片类激动剂发现了这些化学部分的常见几何排列。然后将每种阿片受体类型的激动剂之间的化学和几何共性与最近开发的非特异性阿片识别药效团进行比较。该比较确定了激活 delta、mu 和 kappa 阿片受体的额外要求。距离分析方法能够清楚地区分κ激动剂，同时计算所有化合物的整体分子特性以确定δ和μ受体激活的额外要求。对三组激动剂中每组计算的组合几何和物理化学性质的比较可以确定激活三种阿片受体中每一种的独特要求。这些结果可用于提高已知阿片类激动剂的激活选择性，并作为鉴定具有潜在治疗用途的新型选择性阿片类配体的指南。
Compounds that bind with significant affinity to the opioid receptor types, delta, mu, and kappa, with different combinations of activation and inhibition at these three receptors could be promising behaviorally selective agents. Working on this hypothesis, the chemical moieties common to three different sets of opioid receptor agonists with significant affinity for each of the three receptor types delta, mu, or kappa were identified. Using a distance analysis approach, common geometric arrangements of these chemical moieties were found for selected delta, mu, or kappa opioid agonists. The chemical and geometric commonalities among agonists at each opioid receptor type were then compared with a non-specific opioid recognition pharmacophore recently developed. The comparison provided identification of the additional requirements for activation of delta, mu, and kappa opioid receptors. The distance analysis approach was able to clearly discriminate kappa -agonists, while global molecular properties for all compounds were calculated to identify additional requirements for activation of delta and mu receptors. Comparisons of the combined geometric and physicochemical properties calculated for each of the three sets of agonists allowed the determination of unique requirements for activation of each of the three opioid receptors. These results can be used to improve the activation selectivity of known opioid agonists and as a guide for the identification of novel selective opioid ligands with potential therapeutic usefulness.