Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex.
Curr Pharm Des. 2010 Jan;16(3):344-57. doi: 10.2174/138161210790170067.
The dopaminergic and glutamatergic hypotheses dominate current drug discovery strategies. The dopamine hypothesis states that hyperactivity of the mesolimbic dopaminergic pathway is associated with positive symptoms of the disease, whereas hypoactivity of the mesocortical dopaminergic pathway is associated with the negative and cognitive symptoms. Increasing evidence has also suggested that hypoactivity in the corticolimbic glutamatergic system may contribute to the complex interplay between dysfunctional aspects of these neurotransmitter systems, which could account for much of the symptomatology observed in schizophrenia. Current antipsychotic drugs display moderate efficacy in treating the positive symptoms and limited efficacy against the negative, cognitive, or co-morbidity symptoms of the disease. They are also associated with significant side effects such as extrapyramidal side effects and metabolic disturbances. Thus pharmacologies that are able to more selectively modulate the underlying neuronal substrates of schizophrenia may have utility as efficacious and wide spectrum antipsychotic therapies with potentially improved side effect liabilities. The neuropeptide neuromodulator/neurotransmitter class and their associated receptors have been suggested to be one such family class. One such target which has shown particular promise, and thus has gained much pharmaceutical research interest, is the neurokinin receptor family and particularly the NK(3) receptor. The NK(3) receptor is expressed almost exclusively within the mammalian nervous system and its localisation is commensurate with a role in modulating central monoaminergic neurotransmission. Here we will provide an introduction to both the neurokinin ligands and receptors and review current preclinical understanding of their putative biological roles and, in particular, their modulatory role in the circuitry pertinent to schizophrenia. A brief review of the available chemical strategies employed to produce selective tools and drug development candidates will also be undertaken. Finally we will summarize the available clinical information on those compounds which have progressed into patient populations and evaluate their potential therapeutic utility, and the future of the NK(3) receptor target.
多巴胺能和谷氨酸能假说主导着当前的药物发现策略。多巴胺假说指出，中脑边缘多巴胺能通路的过度活跃与疾病的阳性症状有关，而中脑皮质多巴胺能通路的活动不足与阴性和认知症状有关。越来越多的证据表明，皮质边缘谷氨酸能系统的活动不足可能与这些神经递质系统功能障碍方面的复杂相互作用有关，这可能解释了精神分裂症中观察到的大部分症状。目前的抗精神病药物在治疗阳性症状方面显示出中等疗效，而对疾病的阴性、认知或合并症状的疗效有限。它们还与显著的副作用有关，如锥体外系副作用和代谢紊乱。因此，能够更选择性地调节精神分裂症潜在神经元底物的药理学可能具有作为有效和广谱抗精神病治疗的效用，具有潜在改善的副作用风险。神经肽神经调节剂/神经递质类及其相关受体被认为是这样的一类家族。其中一个特别有希望的靶点，因此引起了广泛的药物研究兴趣，是神经激肽受体家族，特别是 NK(3)受体。NK(3)受体几乎仅在哺乳动物神经系统中表达，其定位与调节中枢单胺能神经传递的作用相一致。在这里，我们将介绍神经激肽配体和受体，并回顾其潜在生物学作用的当前临床前认识，特别是它们在与精神分裂症相关的电路中的调节作用。还将简要回顾用于产生选择性工具和药物开发候选物的可用化学策略。最后，我们将总结已进入患者群体的那些化合物的现有临床信息，并评估其潜在的治疗效用，以及 NK(3)受体靶标的未来。
