Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.
Eur J Pharmacol. 2010 Feb 10;627(1-3):106-14. doi: 10.1016/j.ejphar.2009.10.054. Epub 2009 Oct 30.
Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
激动素 NK(3)受体拮抗剂的临床评估为该靶点在精神分裂症中的治疗效用提供了支持。然而，这些研究并不完全具有结论性，可能是由于这些分子的药代动力学限制。在寻找具有改善特性的激动素 NK(3)受体拮抗剂的过程中，我们发现了 GSK172981 和 GSK256471。这两种化合物对重组人（pK(i)值分别为 7.7 和 8.9）和天然豚鼠（pK(i)值分别为 7.8 和 8.4）激动素 NK(3)受体均具有高亲和力。体外功能评估显示，GSK172981 是克隆人激动素 NK(3)受体的竞争性拮抗剂（pA(2)=7.2），而 GSK256471 减弱了神经激肽 B 诱导的 E(max)反应，表明其具有不可逾越的拮抗剂药理学（pA(2)=9.2）。GSK172981 还在拮抗从豚鼠中脑被盖切片记录的神经激肽 B 刺激的神经元活性方面表现出竞争性特征（表观 pK(B)=8.1），而 GSK256471 则消除了激动剂诱导的反应。GSK172981 和 GSK256471 对中枢神经系统的穿透性通过在中前额皮质中的剂量依赖性激动素 NK(3)受体占有率（分别为 0.8 和 0.9mg/kg，ip 的 ED(50)值）和在豚鼠中剂量依赖性减弱激动剂诱导的“湿狗摇”行为来表明。最后，体内微透析研究表明，急性 GSK172981（30mg/kg，ip）和 GSK256471（1mg/kg，ip）可减轻氟哌啶醇诱导的豚鼠伏隔核细胞外多巴胺的增加。综上所述，这些激动素 NK(3)受体拮抗剂 GSK172981 和 GSK256471 的体外和体内特征支持它们在精神分裂症治疗中的潜在用途。
