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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 ϭ 9.59 -9.90) and rat (pK i ϭ 8.51-9.17) H 3 receptors. GSK189254 is Ͼ10,000-fold selective for human H 3 receptors versus other targets tested, and it exhibited potent functional antagonism (pA 2 ϭ 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC 50 Progressive decline in cognitive performance is a key characteristic of Alzheimer's disease (AD) and related dementias, and improving cognitive function in these diseases represents a complex challenge, given the involvement of numerous neurotransmitter systems and brain regions (CoreyBloom, 2002). Current therapies, such as cholinesterase inhibitors, provide only minimal benefit to a subset of patients and for a limited period, so a number of alternative Article, publication date, and citation information can be found at

We used a mouse with deletion of exons 4, 5, and 6 of the SCN11A (sodium channel, voltage-gated, type XI, ␣) gene that encodes the voltage-gated sodium channel Na v 1.9 to assess its contribution to pain. Na v 1.9 is present in nociceptor sensory neurons that express TRPV1, bradykinin B 2 , and purinergic P2X 3 receptors. In Na v 1.9 ؊/؊ mice, the non-inactivating persistent tetrodotoxin-resistant sodium TTXr-Per current is absent, whereas TTXr-Slow is unchanged. TTXs currents are unaffected by the mutation of Na v 1.9. Pain hypersensitivity elicited by intraplantar administration of prostaglandin E 2 , bradykinin, interleukin-1␤, capsaicin, and P2X 3 and P2Y receptor agonists, but not NGF, is either reduced or absent in Na v 1.9 ؊/؊ mice, whereas basal thermal and mechanical pain sensitivity is unchanged. Thermal, but not mechanical, hypersensitivity produced by peripheral inflammation (intraplanatar complete Freund's adjuvant) is substantially diminished in the null allele mutant mice, whereas hypersensitivity in two neuropathic pain models is unchanged in the Na v 1.9 ؊/؊ mice. Na v 1.9 is, we conclude, an effector of the hypersensitivity produced by multiple inflammatory mediators on nociceptor peripheral terminals and therefore plays a key role in mediating peripheral sensitization.

1 The novel 5-HT 7 receptor antagonist, SB-269970-A, potently displaced [ 3 H]-5-CT from human 5-HT 7(a) (pK i 8.9+0.1) and 5-HT 7 receptors in guinea-pig cortex (pK i 8.3+0.2). 2 5-CT stimulated adenylyl cyclase activity in 5-HT 7(a) /HEK293 membranes (pEC 50 7.5+0.1) and SB-269970-A (0.03 ± 1 mM) inhibited the 5-CT concentration-response with no signi®cant alteration in the maximal response. The pA 2 (8.5+0.2) for SB-269970-A agreed well with the pK i determined from [ 3 H]-5-CT binding studies. 3 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC 50 of 8.4+0.2) was inhibited by SB-269970-A (0.3 mM) with a pK B (8.3+0.1) in good agreement with its antagonist potency at the human cloned 5-HT 7(a) receptor and its binding anity at guinea-pig cortical membranes. 4 5-HT 7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. 5 SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min 71 kg 71). Following a single dose (3 mg kg 71 ) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested.