1. Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats
- Author
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David Matthew Wilson, Alison M. Ray, Andrew D. Medhurst, Robert P. Davis, Ciaran M. Regan, Andrew G. Foley, Teresa Heslop, Sandrine Ociepka, Michael A. Briggs, Trevor White, Barry Crook, Barry Sidney Orlek, Stephen J. Medhurst, Andrew R. Calver, Brenda K. Trail, Iain P. Chessell, Becky Sargent, Tania O. Stean, Joanne Schogger, Neil Upton, Warren D. Hirst, Gordon Bruton, and John B. Davis
- Subjects
Central Nervous System ,Male ,Pyridines ,Scopolamine ,Drinking ,Histamine Antagonists ,Pharmacology ,Biochemistry ,Histamine Agonists ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Avoidance Learning ,medicine ,Animals ,Humans ,Receptors, Histamine H3 ,Inverse agonist ,Receptor ,Analgesics ,Memory Disorders ,Chemistry ,Alkaloid ,Antagonist ,Azepines ,Benzazepines ,Rats ,Allodynia ,Capsaicin ,Pyrazines ,Anesthesia ,Neuralgia ,Cholinergic ,medicine.symptom ,Histamine H3 receptor - Abstract
GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H -3-benzazepin-7-yl)oxy]- N -methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1 H -1,4-diazepine) are novel and selective non-imidazole histamine H 3 receptor antagonists from distinct chemical series with high affinity for human (p K i = 9.67 ± 0.06 and 9.49 ± 0.09, respectively) and rat (p K 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 GTPγS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [ 3 H]- R -α-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 -α-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 3 mg/kg p.o.) and GSK334429 (0.3, 1 and 3 mg/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 1 mg/kg p.o.) and GSK334429 (3 and 10 mg/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.
- Published
- 2007