title: Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.
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.
authors.affiliation: Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. andy.medhurst@gsk.com
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: Michael A
authors.initials: MA
authors.lastname: Briggs
authors.forename: Gordon
authors.initials: G
authors.lastname: Bruton
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Calver
authors.forename: Iain
authors.initials: I
authors.lastname: Chessell
authors.forename: Barry
authors.initials: B
authors.lastname: Crook
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
authors.forename: Robert P
authors.initials: RP
authors.lastname: Davis
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Foley
authors.forename: Teresa
authors.initials: T
authors.lastname: Heslop
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Medhurst
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ociepka
authors.forename: Alison
authors.initials: A
authors.lastname: Ray
authors.forename: Ciaran M
authors.initials: CM
authors.lastname: Regan
authors.forename: Becky
authors.initials: B
authors.lastname: Sargent
authors.forename: Joanne
authors.initials: J
authors.lastname: Schogger
authors.forename: Tania O
authors.initials: TO
authors.lastname: Stean
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Trail
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Trevor
authors.initials: T
authors.lastname: White
authors.forename: Barry
authors.initials: B
authors.lastname: Orlek
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002211:Capsaicin; D002490:Central Nervous System / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D017442:Histamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D006633:Histamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012601:Scopolamine
chemical_list: C519817:1-(1-methylethyl)-4-((1-(6-(trifluoromethyl)-3-pyridinyl)-4-piperidinyl)carbonyl)hexahydro-1H-1,4-diazepine; C519816:5-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-2-pyrazinecarboxamide; D000700:Analgesics; D001381:Azepines; D001552:Benzazepines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D011719:Pyrazines; D011725:Pyridines; D018100:Receptors, Histamine H3; D012601:Scopolamine; D002211:Capsaicin