GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.
6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.
Medhurst
Andrew D
AD
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Ave., Harlow, Essex, CM19 5AW, UK. andy.medhurst@gsk.com
Atkins
Alan R
AR
Beresford
Isabel J
IJ
Brackenborough
Kim
K
Briggs
Michael A
MA
Calver
Andrew R
AR
Cilia
Jackie
J
Cluderay
Jane E
JE
Crook
Barry
B
Davis
John B
JB
Davis
Rebecca K
RK
Davis
Robert P
RP
Dawson
Lee A
LA
Foley
Andrew G
AG
Gartlon
Jane
J
Gonzalez
M Isabel
MI
Heslop
Teresa
T
Hirst
Warren D
WD
Jennings
Carol
C
Jones
Declan N C
DN
Lacroix
Laurent P
LP
Martyn
Abbe
A
Ociepka
Sandrine
S
Ray
Alison
A
Regan
Ciaran M
CM
Roberts
Jennifer C
JC
Schogger
Joanne
J
Southam
Eric
E
Stean
Tania O
TO
Trail
Brenda K
BK
Upton
Neil
N
Wadsworth
Graham
G
Wald
Jeffrey A
JA
White
Trevor
T
Witherington
Jason
J
Woolley
Marie L
ML
Worby
Angela
A
Wilson
David M
DM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004285:Dogs; D017442:Histamine Agonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006633:Histamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018697:Nootropic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000032:analysis / Q000378:metabolism*; D034421:Sus scrofa
D001552:Benzazepines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D018377:Neurotransmitter Agents; D018697:Nootropic Agents; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide