Medhurst Andrew D, Briggs Michael A, Bruton Gordon, Calver Andrew R, Chessell Iain, Crook Barry, Davis John B, Davis Robert P, Foley Andrew G, Heslop Teresa, Hirst Warren D, Medhurst Stephen J, Ociepka Sandrine, Ray Alison, Regan Ciaran M, Sargent Becky, Schogger Joanne, Stean Tania O, Trail Brenda K, Upton Neil, White Trevor, Orlek Barry, Wilson David M
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK.
Biochem Pharmacol. 2007 Apr 15;73(8):1182-94. doi: 10.1016/j.bcp.2007.01.007. Epub 2007 Jan 7.
GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.
GSK207040（5-[(3-环丁基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)氧基]-N-甲基-2-吡嗪甲酰胺）和GSK334429（1-(1-甲基乙基)-4-({1-[6-(三氟甲基)-3-吡啶基]-4-哌啶基}羰基)六氢-1H-1,4-二氮杂卓）是来自不同化学系列的新型选择性非咪唑类组胺H(3)受体拮抗剂，对大脑皮层中表达的人（pK(i)分别为9.67±0.06和9.49±0.09）和大鼠（pK(i)分别为9.08±0.16和9.12±0.14）H(3)受体具有高亲和力。在人重组H(3)受体上，GSK207040和GSK334429是强效功能性拮抗剂（相对于H(3)激动剂诱导的cAMP变化，pA(2)分别为9.26±0.04和8.84±0.04），并表现出反向激动剂特性（相对于基础GTPγS结合，pIC(50)分别为9.20±0.36和8.59±0.04）。口服给药后，GSK207040和GSK334429能有效抑制皮层离体[(3)H]-R-α-甲基组胺结合（ED(50)分别为0.03和0.35mg/kg）。通过阻断大鼠中R-α-甲基组胺诱导的饮水欲，证明了中枢H(3)受体的功能性拮抗作用（GSK207040和GSK334429的口服ID(50)分别为0.02和0.11mg/kg）。在更具病理生理学相关性的药效学模型中，GSK207040（0.1、0.3、1和3mg/kg口服）和GSK334429（0.3、1和3mg/kg口服）在被动回避范式中显著逆转了胆碱能拮抗剂东莨菪碱诱导的失忆。此外，GSK207040（0.1、0.3和1mg/kg口服）和GSK334429（3和10mg/kg口服）显著逆转了辣椒素诱导的爪部退缩阈值降低，首次表明阻断H(3)受体可能能够减轻触觉异常性疼痛。因此，像GSK207040和GSK334429这样的新型H(3)受体拮抗剂不仅在痴呆症中，而且在神经性疼痛中可能具有治疗潜力。
