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cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

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A‐349821 is a selective histamine H3 receptor antagonist/inverse agonist. Herein, binding of the novel non‐imidazole H3 receptor radioligand [3H]A‐349821 to membranes expressing native or recombinant H3 receptors from rat or human sources was characterized and compared with the binding of the agonist [3H]N‐α‐methylhistamine ([3H]NαMH). [3H]A‐349821 bound with high affinity and specificity to an apparent single class of saturable sites and recognized human H3 receptors with 10‐fold higher affinity compared to rat H3 receptors. [3H]A‐349821 detected larger populations of receptors compared to [3H]NαMH. Displacement of [3H]A‐349821 binding by H3 receptor antagonists/inverse agonists was monophasic, suggesting recognition of a single binding site, while that of H3 receptor agonists was biphasic, suggesting recognition of both high‐ and low‐affinity H3 receptor sites. pKi values of high‐affinity binding sites for H3 receptor competitors utilizing [3H]A‐349821 were highly correlated with pKi values obtained with [3H]NαMH, consistent with labelling of H3 receptors by [3H]A‐349821. Unlike assays utilizing [3H]NαMH, addition of GDP had no effect on saturation parameters measured with [3H]A‐349821, while displacement of [3H]A‐349821 binding by the H3 receptor agonist histamine was sensitive to GDP. In conclusion, [3H]A‐349821 labels interconvertible high‐ and low‐affinity states of the H3 receptor, and displays improved selectivity over imidazole‐containing H3 receptor antagonist radioligands. [3H]A‐349821 competition studies showed significant differences in the proportions and potencies of high‐ and low‐affinity sites across species, providing new information about the fundamental pharmacological nature of H3 receptors. British Journal of Pharmacology (2006) 148, 657–670. doi:

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