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

• Published in: The Journal of pharmacology and experimental therapeutics 2012-10, Vol.343 (1), p.233-245
• Main Authors: Esbenshade, Timothy A., Browman, Kaitlin E., Miller, Thomas R., Krueger, Kathleen M., Komater-Roderwald, Victoria, Zhang, Min, Fox, Gerard B., Rueter, Lynne, Robb, Holly M., Radek, Richard J., Drescher, Karla U., Fey, Thomas A., Bitner, R. Scott, Marsh, Kennan, Polakowski, James S., Zhao, Chen, Cowart, Marlon D., Hancock, Arthur A., Sullivan, James P., Brioni, Jorge D.
• Format: Article
• Language: English
• Subjects: Animals; Avoidance Learning - drug effects; Avoidance Learning - physiology; Cognition - drug effects; Cognition - physiology; Guinea Pigs; HEK293 Cells; Histamine H3 Antagonists - chemistry; Histamine H3 Antagonists - pharmacology; Humans; Male; Mice; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Protein Binding - physiology; Pyridazines - chemistry; Pyridazines - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Rats; Rats, Inbred SHR; Rats, Long-Evans; Rats, Sprague-Dawley; Receptors, Histamine H3 - physiology; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.194126

Blockade of the histamine H3 receptor (H3R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H3R antagonist 2-[4′-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H3Rs (Ki = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine 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 H3R 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 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H3R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.