It is widely recognized that histamine is a mediator of itch and recent reports implicate the histamine H4 receptor (H4R) in this response. We have synthesized two novel H4R antagonists, A‐943931 [4‐ ((R) ‐3‐amino‐ pyrrolidin‐1‐yl) ‐6,7‐ dihydro ‐ 5H‐benzo [6,7] cyclohepta [1,2‐d] pyrimidin‐2‐ylamine] and A‐987306 [4‐piperazin‐1‐yl‐5,6,7a,8,9,10,11,11a‐octahydro‐7‐oxa‐1,3‐diaza‐benzo[c] fluoren‐2ylamine] as potent and selective H4R antagonists with high affinity at both human (Kis = 4.6 and 5.7 nM) and rat (Kis = 3.8 and 3.4 nM) receptors, respectively. A‐943931 and A‐987306 competitively and potently antagonize rat H4R agonist‐mediated responses in [35S]GTPγS binding assays (Kbs = 28 and 6 nM) and intracellular calcium mobilization at rat and human receptors (Kbs from 5‐10 nM). When tested in vivo in a mouse model of clobenpropit (10 nM, i.d.) induced scratching, A‐943931 inhibited the scratching response (IC50 = 26 μmoles/kg, i.p.) with significant inhibition (69%) at the highest tested dose (30 μmoles/kg, i.p.). A‐987306 also inhibited the scratching response (IC50 = 0.4 μmoles/kg, i.p.) with (85%) inhibition seen at 30 μmoles/kg, i.p. Our results show that A‐943931 and A‐987306 are potent and selective H4R antagonists with robust antipruritic activity and are useful tools for further exploration of the role of H4R receptors in vivo. Research supported by Abbott Laboratories.