Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3 Receptor Antagonist

Blockade of the histamine H 3 receptor (H 3 R) enhances central neurotransmitter release, making this an attractive target for the treatment of cognitive disorders. Here we present the in vitro and in vivo pharmacological profiles for the H 3 R antagonist ABT-288 (2-[49-((3aR,6aR)-5-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H 3 Rs (K i s = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H 3 R receptor occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37-66%, with a wide CNS and cardiovascular safety margin. Thus, ABT-288 is a selective H 3 R antagonist with broad pro-cognitive efficacy in rodents and excellent drug-like properties to support its advancement to the clinical area.