H3 antagonists increase the release of brain histamine, ACh, NE and DA, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine support the effect on attention and vigilance, but histamine also modulates other cognitive domains like short-term and long-term memory. A number of H3 antagonists including BF2.649, PF-03654746, GSK189254, MK-0249, JNJ-17216498 and ABT-288 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 ADHD and schizophrenic patients. Preclinical studies have also shown that H3 antagonists activate intracellular signaling pathways that may improve cognitive efficacy as well as disease modifying effects in Alzheimer's. Ongoing clinical studies will be able to determine the utility of H3 antagonists for the treatment of cognitive disorders in humans.
- Received May 17, 2010.
- Revision received July 23, 2010.
- Accepted July 23, 2010.
- The American Society for Pharmacology and Experimental Therapeutics