Street L J, Baker R, Castro J L, Chambers M S, Guiblin A R, Hobbs S C, Matassa V G, Reeve A J, Beer M S, Middlemiss D N
Chemistry Department, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
J Med Chem. 1993 May 28;36(11):1529-38. doi: 10.1021/jm00063a003.
The synthesis and 5-HT1D receptor activity of a novel series of 5-(oxadiazolyl)tryptamines is described. Modifications of the oxadiazole 3-substituent, length of the linking chain (n), and the amine substituents are explored and reveal a large binding pocket in the 5-HT1D receptor domain. Oxadiazole substituents such as benzyl are accommodated without loss of agonist potency or efficacy. The incorporation of polar functionality on a phenyl or benzyl spacer group results in a 10-fold increase in affinity and functional potency. Optimal 5-HT1D activity is observed when the heterocycle is conjugated with the indole and the benzyl sulfonamides 20t and 20u represent some of the most potent 5-HT1D agonists known. Replacement of O for S in the heterocycle leads to a further increase in potency. Deletion of oxadiazole N-2 does not reduce activity, suggesting the requirement for only one H-bond acceptor in this location. The selectivity of these compounds for 5-HT1D receptors over other serotonergic receptors is discussed. Sulfonamide 20t shows > or = 1000-fold selectivity for 5-HT1D over 5-HT2, 5-HT1C, and 5-HT3 receptors and 10-fold selectivity with respect to 5-HT1A receptors. The functional activity of this series of compounds is studied and demonstrates high 5-HT1D receptor potency and efficacy comparable to that of 5-HT.
描述了一系列新型5-(恶二唑基)色胺的合成及5-HT1D受体活性。对恶二唑3-取代基、连接链长度(n)和胺取代基进行了修饰，结果表明5-HT1D受体结构域存在一个大的结合口袋。苄基等恶二唑取代基能够被容纳，且激动剂效力和效能不会丧失。在苯基或苄基间隔基团上引入极性官能团会使亲和力和功能效力提高10倍。当杂环与吲哚共轭时可观察到最佳的5-HT1D活性，苄基磺酰胺20t和20u代表了一些已知的最有效的5-HT1D激动剂。杂环中O被S取代会导致效力进一步提高。删除恶二唑N-2不会降低活性，这表明该位置仅需一个氢键受体。讨论了这些化合物对5-HT1D受体相对于其他5-羟色胺能受体的选择性。磺酰胺20t对5-HT1D的选择性比对5-HT2、5-HT1C和5-HT3受体高≥1000倍，相对于5-HT1A受体有10倍的选择性。研究了该系列化合物的功能活性，结果表明其对5-HT1D受体具有高效力和效能，与5-HT相当。
