Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Kraków, Poland.
Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Kraków, Poland.
Bioorg Med Chem Lett. 2021 Jun 15;42:128028. doi: 10.1016/j.bmcl.2021.128028. Epub 2021 Apr 9.
Schizophrenia and depression are diseases that significantly impede human functioning in society. Current antidepressant drugs are not fully effective. According to literature data, the effect on DR or 5-HTR can effectively reduce the symptoms of depression or schizophrenia. Recent research hypothetized that the synergism of both of these receptors can improve the effectiveness of therapy. Ipsapirone, a representative of long-chain arylpiperazines, is a known 5-HTR ligand that has antidepressant effect. This compound has no affinity for the DR. Bearing in mind, we decided to design ligands with improved affinity to DR and confirmed that in some cases elongation of the carbon linker or arylpiperazine exchange may have beneficial influence on the binding to D2R and 5-HT1AR. Four groups of ligands being ipsapirone analogues with butyl, pentyl, hexyl and stiffened xylene chains were designed. All compounds were obtained in solvent-free reactions supported by a microwave irradiation with an efficiency mainly above 60%. All ligands containing 1-(2-pyrimidinyl)piperazine exhibited high affinity to 5-HTR. In this case, chemical modifications within the chain did not affect the affinity to DR. In the case of ligands containing 1-phenylpiperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(1-naphthyl)piperazine, and 1-(4-chlorophenyl)piperazine, elongation of carbon linker increases of affinity to DR. For ligands containing 1- (2-pyridyl) piperazine, and 1-(2,3-dichlorophenyl)piperazine, we observed an opposite effect. For ligands containing 1-phenylpiperazine, 1-(2-methoxyphenyl)piperazine and 1-(2-pyridyl)piperazine, chain elongation had no effect on 5-HTR binding. In turn of ligands containing 1-(3-trifluoromethylphenyl)piperazine and 1- (2,3-dichlorophenyl)piperazine, we observed that elongation of carbon linker has a positive influence to 5-HTR. Molecular modelling was used to support the SAR study.
精神分裂症和抑郁症是严重妨碍人类在社会中正常功能的疾病。目前的抗抑郁药物并非完全有效。根据文献数据，对 DR 或 5-HTR 的作用可以有效地减轻抑郁或精神分裂症的症状。最近的研究假设，这两种受体的协同作用可以提高治疗的效果。伊沙匹隆是长链芳基哌嗪的代表，是一种已知的 5-HTR 配体，具有抗抑郁作用。这种化合物对 DR 没有亲和力。考虑到这一点，我们决定设计对 DR 具有改善亲和力的配体，并证实在某些情况下，延长碳键或芳基哌嗪的交换可能对与 D2R 和 5-HT1AR 的结合有有益的影响。设计了四组作为伊沙匹隆类似物的配体，带有丁基、戊基、己基和刚性二甲苯链。所有化合物都在无溶剂反应中获得，反应在微波辐射的支持下进行，效率主要高于 60%。所有含有 1-(2-嘧啶基)哌嗪的配体对 5-HTR 表现出高亲和力。在这种情况下，链内的化学修饰不影响对 DR 的亲和力。对于含有 1-苯基哌嗪、1-(3-三氟甲基苯基)哌嗪、1-(1-萘基)哌嗪和 1-(4-氯苯基)哌嗪的配体，碳键的延长增加了对 DR 的亲和力。对于含有 1-(2-吡啶基)哌嗪和 1-(2,3-二氯苯基)哌嗪的配体，我们观察到相反的效果。对于含有 1-苯基哌嗪、1-(2-甲氧基苯基)哌嗪和 1-(2-吡啶基)哌嗪的配体，链的延长对 5-HTR 结合没有影响。对于含有 1-(3-三氟甲基苯基)哌嗪和 1-(2,3-二氯苯基)哌嗪的配体，我们观察到碳键的延长对 5-HTR 有积极的影响。分子建模用于支持 SAR 研究。
