Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H(1)  and H(3)  receptors.
OBJECTIVE
Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist.


METHODS
GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography.


RESULTS
In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h.


CONCLUSIONS
GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.
Respiratory Biology, Respiratory CEDD, GlaxoSmithKline, Stevenage, UK.
R J
RJ
Slack
L J
LJ
Russell
D A
DA
Hall
M A
MA
Luttmann
A J
AJ
Ford
K A
KA
Saunders
S T
ST
Hodgson
H E
HE
Connor
C
C
Browning
K L
KL
Clark
D000485:Allergens; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001667:Binding, Competitive; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010047:Ovalbumin; D010793:Phthalazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012221:Rhinitis, Allergic, Perennial; D014162:Transfection
D000485:Allergens; D001552:Benzazepines; C558853:GSK 1004723; D006634:Histamine H1 Antagonists; D054828:Histamine H3 Antagonists; D010793:Phthalazines; D010880:Piperidines; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide; D006632:Histamine; D002217:Carbachol; D010047:Ovalbumin; D011738:Pyrilamine