Raviña E, Casariego I, Masaguer C F, Fontenla J A, Montenegro G Y, Rivas M E, Loza M I, Enguix M J, Villazon M, Cadavid M I, Demontis G C
Departamento de Quimica Organica, Laboratorio de Quimica Farmaceutica, Universidad de Santiago, E-15706 Santiago de Compostela, Spain.
J Med Chem. 2000 Nov 30;43(24):4678-93. doi: 10.1021/jm0009890.
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo[b]furan-4-ones bearing 4-(6-fluorobenzisoxazolyl)piperidine, 4-(p-fluorobenzoyl)piperidine, 4-(o-methoxyphenyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, or linear butyro(or valero)phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D(1), D(2), D(4)) and serotonin receptors (5-HT(2A), 5-HT(2B), 5-HT(2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT(2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(p-fluorobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs.
制备了一系列新型构象受限的丁酰苯类化合物（带有4-(6-氟苯并异恶唑基)哌啶、4-(对氟苯甲酰基)哌啶、4-(邻甲氧基苯基)哌嗪、4-(2-吡啶基)哌嗪、4-(2-嘧啶基)哌嗪或直链丁酰（或戊酰）苯片段的6-氨甲基-4,5,6,7-四氢苯并[b]呋喃-4-酮），并通过体外测定对多巴胺受体（D(1)、D(2)、D(4)）和5-羟色胺受体（5-HT(2A)、5-HT(2B)、5-HT(2C)）的亲和力、神经化学研究以及体内测定抗精神病潜力和诱发锥体外系副作用的风险，将其作为抗精神病药物进行评估。效力和选择性主要取决于连接到环己酮结构上的胺片段。带有苯甲酰哌啶部分的化合物20b和带有苯并异恶唑基片段的化合物20c对5-HT(2A)受体具有选择性。N-[(4-氧代-4,5,6,7-四氢苯并[b]呋喃-6-基)甲基]-4-(对氟苯甲酰基)哌啶（20b，QF1003B）和N-[(4-氧代-4,5,6,7-四氢苯并[b]呋喃-6-基)甲基]-4-(6-氟苯并异恶唑-3-基)哌啶（20c，QF1004B）的体外和体内药理学特征表明它们可能作为抗精神病（神经安定）药物有效。
