Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2007-3-20
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
73
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1182-94
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:17276409-Analgesics, pubmed-meshheading:17276409-Animals, pubmed-meshheading:17276409-Avoidance Learning, pubmed-meshheading:17276409-Azepines, pubmed-meshheading:17276409-Benzazepines, pubmed-meshheading:17276409-Capsaicin, pubmed-meshheading:17276409-Central Nervous System, pubmed-meshheading:17276409-Drinking, pubmed-meshheading:17276409-Histamine Agonists, pubmed-meshheading:17276409-Histamine Antagonists, pubmed-meshheading:17276409-Humans, pubmed-meshheading:17276409-Male, pubmed-meshheading:17276409-Memory Disorders, pubmed-meshheading:17276409-Neuralgia, pubmed-meshheading:17276409-Pyrazines, pubmed-meshheading:17276409-Pyridines, pubmed-meshheading:17276409-Rats, pubmed-meshheading:17276409-Rats, Sprague-Dawley, pubmed-meshheading:17276409-Receptors, Histamine H3, pubmed-meshheading:17276409-Scopolamine Hydrobromide
pubmed:year
2007
pubmed:articleTitle
Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.
pubmed:affiliation
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. andy.medhurst@gsk.com
pubmed:publicationType
Journal Article