Perrone R, Berardi F, Colabufo N A, Leopoldo M, Tortorella V, Fiorentini F, Olgiati V, Ghiglieri A, Govoni S
Dipartimento Farmaco-chimico, Università di Bari, Italy.
J Med Chem. 1995 Mar 17;38(6):942-9. doi: 10.1021/jm00006a013.
Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.
为了提高对5-HT1A相对于D-2、α1、σ及其他5-HT受体的选择性，合成了几种在侧链末端带有四氢萘部分的4-烷基-1-芳基哌嗪。对3型（1-芳基-4-[3-(1,2-二氢萘-4-基)-正丙基]哌嗪）的先前结构进行了许多改变。根据侧链上双键和杂原子的有无，采用了几种合成方法来获得最终产物。在第一种情况下，广泛使用了格氏反应，而在第二种情况下，则采用了常规的合成方法。通过放射性受体结合试验评估了最终化合物对多巴胺D-1和D-2、5-羟色胺5-HT1A、5-HT1B、5-HT1C和5-HT2、α1肾上腺素能和σ受体的体外活性。对于2-甲氧基苯基、2-吡啶基和未取代苯基的N-哌嗪衍生物，在5-HT1A受体上观察到低IC50值（0.3 nM）和高选择性值。
