P3‐354: ABT‐288, a potent and selective histamine H3 receptor antagonist, facilitates attention and memory in preclinical models

Background: The histamine H3 receptor is highly expressed in human cortex, hippocampus, and hypothalamus, brain regions that are associated with cognitive processing. Histamine H3 receptor antagonists can block H3 autoreceptors to enhance the central release of histamine as well as block H3 heteroreceptors to enhance the release of ACh, NE, and DA; neurotransmitters involved in vigilance, alertness, and cognition. The development of compounds selective for the human histamine H3 receptor may provide a novel approach for the treatment of cognitive disorders. Methods: Histamine H3 antagonists were evaluated in several behavioral tests including the five-trial inhibitory avoidance in SHR rat pups, social recognition in adult rats, and spatial memory in the water maze in rats. In vivo brain occupancy of H3 receptors was measured using [ H]-A-349821. In vivo release of brain neurotransmitters was measured in conscious rats implanted with microdialysis probes in the prefrontal cortex. Results: ABT-288 is a novel, potent and selective antagonist of human and rat histamine H3 receptors (Ki 1⁄4 1.9 and 8.2 nM, respectively). After systemic administration ABT-288 enhances the release of histamine, ACh, and DA in the rat prefrontal cortex. ABT-288 improves attention in the five-trial inhibitory avoidance test, social memory in rats, and spatial memory in the water maze test. In vivo brain H3 receptor occupancy of ABT288 in rats corresponded to the plasma levels in the behavioral models. ABT288 activates rat slow-wave EEG at doses higher than the pro-cognitive doses, exhibits a wide CNS and cardiovascular safety margin, and good pharmacokinetic properties. H3 antagonists like ABT-239 also activates intracellular signaling processes suggestive of disease-modifying efficacy in Alzheimer’s. Conclusions: ABT-288 is a selective and potent histamine H3 antagonist with drug-like properties and broad efficacy across animal cognition models suggesting potential clinical efficacy for the treatment of cognitive disorders such as ADHD, cognitive deficits of schizophrenia and Alzheimer’s disease.