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Histamine H3 receptors exist in the presynapse of histaminergic nerve terminals, and they regulate the synthesis and release of histamine. A high density of histamine H3 receptors is observed in the cerebral cortex, the amygdala, the striatum, the hippocampus, the thalamus and the hypothalamus. In this review, we describe signal transduction mechanisms of histamine H3 receptors and discuss the structure-activity relationship of histamine H3-receptor ligands, including new compounds that possess high selectivities and affinities. Possible roles of histamine H3 receptors on neurobehavioral disorders such as Alzheimer's disease, Down syndrome, attention deficit hyperactive disease, epilepsy, stress, anxiety, Parkinson's disease, etc. were also described. Recent pharmacological studies revealed that BP2.94, a histamine H3 receptor agonist, has anti-inflammatory and analgesic action. BP2.94 may be useful for the treatment of migraine and is now in clinical trial. Histamine H3 receptor antagonists such as GT2016 and FUB181 may provide clinical candidates for the treatment of dementia, attention deficit hyperactive disorder and epilepsy.

The roles of histamine H3 receptors in the behavioral disorders and neuropsychopharmacological aspects of its ligands in the brain.