A-987306 is a new histamine H(4) antagonist. A-987306 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. A-987306 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 umol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain. A-987306 inhibited the scratching response (IC50 = 0.4 umoles/kg, i.p.) with (85%) inhibition seen at 30 umoles/kg, i.p. A-987306 is a potent and selective H4R antagonist with robust antipruritic activity and is a useful tool for further exploration of the role of H4R receptors in vivo.