Back to Search
Start Over
Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2007 Apr 15; Vol. 73 (8), pp. 1182-94. Date of Electronic Publication: 2007 Jan 07. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Analgesics pharmacokinetics
Analgesics pharmacology
Analgesics therapeutic use
Animals
Avoidance Learning drug effects
Azepines administration & dosage
Azepines pharmacokinetics
Benzazepines pharmacokinetics
Benzazepines pharmacology
Central Nervous System drug effects
Drinking drug effects
Histamine Agonists pharmacokinetics
Histamine Agonists pharmacology
Histamine Antagonists pharmacokinetics
Histamine Antagonists pharmacology
Humans
Male
Memory Disorders chemically induced
Neuralgia chemically induced
Pyrazines pharmacokinetics
Pyrazines pharmacology
Pyridines administration & dosage
Pyridines pharmacokinetics
Rats
Rats, Sprague-Dawley
Azepines therapeutic use
Benzazepines therapeutic use
Capsaicin
Histamine Antagonists therapeutic use
Memory Disorders drug therapy
Neuralgia drug therapy
Pyrazines therapeutic use
Pyridines therapeutic use
Receptors, Histamine H3 metabolism
Scopolamine
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 73
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17276409
- Full Text :
- https://doi.org/10.1016/j.bcp.2007.01.007