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The Evolution of Histamine H3 Antagonists/Inverse Agonists

[ Vol. 11 , Issue. 6 ]


Evan P. Lebois, Carrie K. Jones and Craig W. Lindsley   Pages 648 - 660 ( 13 )


This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H3 antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimers disease, neuropathic pain and ADHD. Within the two main classes of H3 ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H3 ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H3R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H3R antagonists/inverse agonists.


GPCR, H3, histamine, ADHD, schizophrenia, sleep/wake, obesity, Alzheimer's disease, epilepsy, efficacy, scaffolds, allosteric modulators


Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232 USA.

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