Cortizo L, Santana L, Ravina E, Orallo F, Fontenla J A, Castro E, Calleja J M, de Ceballos M L
Faculty of Pharmacy, University of Santiago de Compostela, Spain.
J Med Chem. 1991 Jul;34(7):2242-7. doi: 10.1021/jm00111a046.
Starting from beta-benzoylpropionic acid we synthesized 3-(aminomethyl)tetralones in which the amino substituent was 4-(N-piperazinyl)-p-fluorobutyrophenone, 4-benzoylpiperidine, 4-hydroxy-4-phenylpiperidine or 4-(o-methoxyphenyl)piperazine. The possible dopamine antagonist activity of these compounds was investigated in both "in vitro" and "in vivo" experiments. These compounds potently inhibited [3H]spiperone binding to D2 striatal receptors and moderately inhibited [3H]SCH-23390 binding to D1 striatal receptors (Kis in the nanomolar and micromolar ranges, respectively). Apomorphine-induced stereotypies and amphetamine group toxicity were antagonized, to different extents, by the compounds under study, with a potency similar to that of haloperidol. Interestingly, no catalepsy was observed after administration of the new compounds (2-8 mg/kg). The most active compounds "in vivo" 14 and 15 possessed two butyrophenone pharmacophores. However, the tetralone moiety appeared not critical for their antidopaminergic activity, since all target compounds were less active than haloperidol. These studies provide a pharmacological basis for future research on these new compounds devoid of cataleptogenic activity.
我们从β-苯甲酰丙酸出发，合成了3-(氨甲基)四氢萘酮，其中氨基取代基为4-(N-哌嗪基)-对氟丁酰苯、4-苯甲酰哌啶、4-羟基-4-苯基哌啶或4-(邻甲氧基苯基)哌嗪。在“体外”和“体内”实验中研究了这些化合物可能的多巴胺拮抗活性。这些化合物能有效抑制[3H]司来吉兰与纹状体D2受体的结合，并适度抑制[3H]SCH-23390与纹状体D1受体的结合（Ki分别在纳摩尔和微摩尔范围内）。所研究的化合物不同程度地拮抗了阿扑吗啡诱导的刻板行为和苯丙胺组毒性，其效力与氟哌啶醇相似。有趣的是，给予新化合物（2-8毫克/千克）后未观察到僵住症。“体内”活性最高的化合物14和15具有两个丁酰苯药效基团。然而，四氢萘酮部分对其抗多巴胺能活性似乎并不关键，因为所有目标化合物的活性均低于氟哌啶醇。这些研究为未来对这些无致僵活性的新化合物的研究提供了药理学依据。
