FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia
FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia
复制标题
DOI：
10.1007/s00213-004-1782-1
复制
发表时间：
2004-08-01
影响因子：
3.4
通讯作者：
Feldon, J
中科院分区：
文献类型：
--
作者：
Boeckler, F;Russig, H;Feldon, J
理由。2-[4-（4-氯苯基）哌嗪-1-基甲基]吡唑并[1，5-a]吡啶（FAUC 213）是多巴胺D-4受体亚型的高选择性拮抗剂。它被设计为两种部分拮抗剂的衍生物，并已在有丝分裂试验中被证明是完全拮抗剂。目标.在本研究中，在行为神经生物学和神经化学的动物模型中检查FAUC 213的抗精神病特性。方法.筛选不同浓度的FAUC 213对自发的以及安非他明诱导的自发活动和阿朴吗啡诱导的前脉冲中断的影响。在木僵模型中，通过高效液相色谱法（HPLC）检测几个脑区的多巴胺周转率，研究了引起锥体外系副作用的可能性。通过HPLC-药代动力学研究验证了应用时间表，并测定了化合物的生物利用度。结果在30 mg/kg剂量下，发现在减少安非他明诱导的运动过度活跃和恢复阿扑吗啡破坏的前脉冲抑制方面具有显著作用。这个剂量被证明不足以诱发僵住症或增加背侧纹状体、中脑核和内侧前额叶皮质的多巴胺周转。因此，不认为选择性D-4拮抗剂FAUC 213通过D-2受体拮抗作用介导上述作用，但目前不能排除5-HT 2-和α（1）-受体的部分参与。结论.我们已经收集到的证据表明，FAUC 213表现出非典型的抗精神病药物的特点。
Rationale. 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D-4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives. In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods. Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results. A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D-4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D-2 receptor antagonism, but a partial involvement of 5-HT2- and alpha(1)-receptors cannot be ruled out at present. Conclusions. We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.