Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system.
Evidence exists to implicate the monoamine histamine in the control of arousal and cognitive functions. Antagonists of H(3) receptors are postsynaptic and presynaptic modulators of neural transmission in a variety of neuronal circuits relevant to cognition. Accumulating neuroanatomical, neurochemical, pharmacological, and behavioral data support the idea that H(3) receptor antagonists may function to improve cognitive performances in disease states (e.g., Alzheimer's disease and mild cognitive impairment states). Thus, H(3) receptor antagonists have been shown to increase performance in attention and memory tests in nonhuman experiments and prevent the degradation in performances produced by scopolamine, MK-801, or age. In contrast, agonists of the H(3) receptor generally produce cognitive impairing effects in animal models. The role of H(3) receptors in these behavioral effects is substantiated by data indicating a central origin for their effects, the selectivity of some of the H(3) receptor antagonists studied, and the pharmacological modification of effects of H(3) receptor antagonists by selective H(3) receptor agonists. Data and issues that challenge the potential role for H(3) receptor antagonists in cognitive processes are also critically reviewed. H(3) receptor antagonists may also have therapeutic value in the management of obesity, pain, sleep disorders, schizophrenia, and attention deficit hyperactivity disorder.
Witkin
J M
JM
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA. jwitkin@lilly.com
Nelson
D L
DL
D000818:Animals; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000627:therapeutic use*; D006801:Humans; D018100:Receptors, Histamine H3 / Q000502:physiology*
D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; D006632:Histamine