Neuroscience, Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium.
J Pharmacol Exp Ther. 2012 Jul;342(1):91-105. doi: 10.1124/jpet.111.190702. Epub 2012 Apr 6.
All marketed antipsychotics act by blocking dopamine D(2) receptors. Fast dissociation from D(2) receptors may be one of the elements contributing to the lower incidence of extrapyramidal symptoms (EPS) exhibited by newer antipsychotics. Therefore, we screened for specific D(2) receptor blockers with a fast rate of dissociation. Radioligand binding experiments identified N-[1-(3,4-difluorobenzyl)piperidin-4-yl]-6-(trifluoromethyl)pyridazin-3-amine (JNJ-37822681) as a fast-dissociating D(2) ligand. Its D(2) receptor specificity was high compared with atypical antipsychotics, with little activity at receptors associated with unwanted effects [α(1), α(2), H(1), muscarinic, and 5-hydroxytryptamine (5-HT) type 2C] and for receptors that may interfere with the effects of D(2) antagonism (D(1), D(3), and 5-HT(2A)). JNJ-37822681 occupied D(2) receptors in rat brain at relatively low doses (ED(50) 0.39 mg/kg) and was effective in animal models of psychosis (e.g., inhibition of apomorphine-induced stereotypy or D-amphetamine/phencyclidine-induced hyperlocomotion). Prolactin levels increased from an ED(50) (0.17 mg/kg, peripheral D(2) receptors) close to the ED(50) required for apomorphine antagonism (0.19 mg/kg, central D(2) receptors), suggesting excellent brain disposition and minimal prolactin release at therapeutic doses. JNJ-37822681 induced catalepsy and inhibited avoidance behavior, but with a specificity margin relative to apomorphine antagonism that was larger than that obtained for haloperidol and similar to that obtained for olanzapine. This larger specificity margin (compared with haloperidol) may reflect lower EPS liability and less behavioral suppression after JNJ-37822681. JNJ-37822681 is a novel, potent, specific, centrally active, fast-dissociating D(2) antagonist with optimal brain disposition, and it is the first compound that allows the evaluation of the potential value of fast D(2) antagonism for the treatment of schizophrenia and bipolar disorder.
所有市售的抗精神病药物都是通过阻断多巴胺 D2 受体起作用的。快速与 D2 受体解离可能是新型抗精神病药物导致锥体外系症状（EPS）发生率较低的原因之一。因此，我们筛选了具有快速解离率的特定 D2 受体阻滞剂。放射配体结合实验鉴定出 N-[1-(3,4-二氟苄基)哌啶-4-基]-6-(三氟甲基)哒嗪-3-胺（JNJ-37822681）为快速解离的 D2 配体。与非典型抗精神病药物相比，它对 D2 受体具有很高的特异性，对与不良反应相关的受体（α1、α2、H1、毒蕈碱和 5-羟色胺 2C 型）和可能干扰 D2 拮抗作用的受体（D1、D3 和 5-羟色胺 2A 型）几乎没有活性。JNJ-37822681 以相对较低的剂量（ED50 为 0.39mg/kg）占据大鼠脑中的 D2 受体，并且在精神病动物模型中有效（例如，抑制阿扑吗啡诱导的刻板行为或 D-苯丙胺/苯环利定诱导的过度活动）。催乳素水平从接近阿扑吗啡拮抗作用所需的 ED50（0.19mg/kg，中枢 D2 受体）的 ED50（0.17mg/kg，外周 D2 受体）增加，表明在治疗剂量下具有良好的脑分布和最小的催乳素释放。JNJ-37822681 引起僵住和抑制回避行为，但与阿扑吗啡拮抗作用的特异性边缘相比，其特异性边缘大于氟哌啶醇，与奥氮平相似。这种更大的特异性边缘（与氟哌啶醇相比）可能反映了 JNJ-37822681 后较低的 EPS 倾向和较少的行为抑制。JNJ-37822681 是一种新型、有效、特异、中枢活性、快速解离的 D2 拮抗剂，具有最佳的脑分布，是第一个可以评估快速 D2 拮抗作用治疗精神分裂症和双相情感障碍潜在价值的化合物。
