Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.
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.
Medhurst
Andrew D
AD
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. andy.medhurst@gsk.com
Briggs
Michael A
MA
Bruton
Gordon
G
Calver
Andrew R
AR
Chessell
Iain
I
Crook
Barry
B
Davis
John B
JB
Davis
Robert P
RP
Foley
Andrew G
AG
Heslop
Teresa
T
Hirst
Warren D
WD
Medhurst
Stephen J
SJ
Ociepka
Sandrine
S
Ray
Alison
A
Regan
Ciaran M
CM
Sargent
Becky
B
Schogger
Joanne
J
Stean
Tania O
TO
Trail
Brenda K
BK
Upton
Neil
N
White
Trevor
T
Orlek
Barry
B
Wilson
David M
DM
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
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