Moon M W, Morris J K, Heier R F, Chidester C G, Hoffmann W E, Piercey M F, Althaus J S, Von Voigtlander P F, Evans D L, Figur L M
Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
J Med Chem. 1992 Mar 20;35(6):1076-92. doi: 10.1021/jm00084a013.
The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.
本文描述了5-(二丙基氨基)-5,6-二氢-4H-咪唑并[4,5,1-ij]喹啉-2(1H)-酮(5)的合成，该化合物是一种强效多巴胺D2激动剂，对多巴胺/5-羟色胺(5HT1A)具有高选择性。多巴胺能活性与5的(R)-对映体相关；(S)-对映体无多巴胺能活性。制备了一系列咪唑啉酮环被修饰为各种5或6元杂环的类似物。其中一些化合物兼具多巴胺能和5-羟色胺能活性，而一种化合物6-(二丙基氨基)-1,2,6,7-四氢-3H,5H-吡啶并[3,2,1-ij]喹唑啉-3-酮(24)是一种选择性5-羟色胺能激动剂。还制备了5的二丙基胺取代基被修饰的各种类似物。其中大多数显示出多巴胺能活性降低，而有几种在5-羟色胺5HT1A受体上与5具有相同的效力。文中提出了新化合物在多巴胺和5-羟色胺受体上的取向，并与已知对这些受体具有高亲和力的其他三环配体的取向进行了比较。
