Pyrrolo [1,3] benzothiazepine-based 5 -羟色胺和多巴胺受体拮抗剂。分子建模、进一步结构活性关系的研究,识别新型非典型抗精神病药物。
文章的细节
-
引用
复制到剪贴板 -
Campiani G, Butini年代,Fattorusso C, Catalanotti B,吉玛年代,Nacci V, Morelli E, Cagnotto, Mereghetti我Mennini T, Carli M, Minetti P,迪切萨雷·马Mastroianni D, Scafetta N, Galletti B,史塔西马,Castorina M, Pacifici L, Vertechy M, Di Serio年代,Ghirardi O,开始啊,Carminati P
Pyrrolo [1,3] benzothiazepine-based 5 -羟色胺和多巴胺受体拮抗剂。分子建模、进一步结构活性关系的研究,识别新型非典型抗精神病药物。
J医学杂志。2004年1月1;47 (1):143 - 57。
- PubMed ID
-
14695828 (在PubMed]
- 文摘
-
最近我们报道的药理特性,10-dihydropyrrolo [1,3] benzothiazepine导数(S) -(+) 8作为一种新型非典型抗精神病剂。这种化合物有一个最佳pK (i) 5 (2) / D(2)比例为1.21 (pK (i) 5 (2) = 8.83;pK (i) D (2) = 7.79)。低维(2)受体的亲和力(S) -(+) 8相比,其对映体是解释为难以达到所需的构象优化满足D(2)药效团。寻找新的非典型抗精神病药物的目的我们进一步调查的核心结构(S) -(+) 8,合成类似物与特定的取代基;(SAR)的结构活性关系研究也扩大了与其他的设计和合成类似物,其特征为pyrrolo [2, 1 b] [1,3] benzothiazepine骨架,代替benzo-fused环或吡咯体系。9,10-dihydro类似吡咯环上的取代基引入被有害的亲和力为多巴胺和5 - (2 a)受体,但引入双键C-9/10的结构(S) -(+) 8导致的D (2) / 5 - (2 a)受体配体与一个典型的绑定配置文件(9 f, pK (i) 5 (2) / D(2)的比率1.01,日志Y = 8.43)。然后,减少D(2)受体亲和力和恢复了不饱和类似物,我们利用的影响具体的三环系统替换9 f。通过分子建模方法生成的一系列小说的潜在的非典型抗精神病药物,优化5 ht (2) / D(2)受体亲和力比率,比参考易于合成和纯化化合物(S) - (+) 8。SAR趋势识别,和类似物合成和测试中绑定化验,9 D和9米被当成最有趣,给非典型logy得分分别为4.98和3.18 (pK (i) 5 (2) / D(2)比率为1.20和1.30,分别)。 They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.