Wermuth C G, Schlewer G, Bourguignon J J, Maghioros G, Bouchet M J, Moire C, Kan J P, Worms P, Biziere K
Departement de Pharmacochimie Moléculaire, Centre de Neurochimie du CNRS, Université Louis Pasteur, Strasbourg, France.
J Med Chem. 1989 Mar;32(3):528-37. doi: 10.1021/jm00123a004.
Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.
米那普明[3-[(β-吗啉代乙基)氨基]-4-甲基-6-苯基哒嗪二盐酸盐]在大多数抑郁症动物模型中具有活性，并且在体内表现出双重拟多巴胺能和拟5-羟色胺能活性特征。为了分离这两种效应并确定相关的结构要求，合成了一系列47种结构多样的米那普明取代类似物，并测试了它们潜在的抗抑郁、5-羟色胺能和多巴胺能活性。构效关系表明，多巴胺能和5-羟色胺能活性可以分离。5-羟色胺能活性似乎主要与哒嗪环4位上的取代基相关，而多巴胺能活性似乎取决于哒嗪环6位上对位羟基化芳环的存在或形成。
