JPET Miniseries: H3 Receptors Discovery of Histamine H3 Antagonists for the Treatment of Cognitive Disorders and Alzheimer’s Disease

H3 antagonists increase the release of brain histamine, acetylcholine, noradrenaline, and dopamine, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine supports the effect on attention and vigilance, but histamine also modulates other cognitive domains such as shortterm and long-term memory. A number of H3 antagonists, including 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride (BF2.649), (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1ylmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-Nmethyl-3-pyridinecarboxamide hydrochloride (GSK189254), MK0249 (structure not yet disclosed), JNJ-17216498 (structure not yet disclosed), and ABT-288 (structure not yet disclosed), have advanced to the clinical area for the potential treatment of human cognitive disorders. H3 antagonists exhibited wake-promoting effects in humans and efficacy in narcoleptic patients, indicating target engagement, but some of them were not efficacious in patients suffering from attention-deficit hyperactivity disorder and schizophrenic patients. Preclinical studies have also shown that H3 antagonists activate intracellular signaling pathways that may improve cognitive efficacy and disease-modifying effects in Alzheimer’s disease. Ongoing clinical studies will be able to determine the utility of H3 antagonists for the treatment of cognitive disorders in humans.