cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine(A-987306), A New Histamine H4R Antagonist that Blocks Pain Responses against Carrageenan-Induced Hyperalgesia

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 ED50 of 42 mu mol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.