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454721 
Journal Article 
Histamine H-3 receptor antagonists: From target identification to drug leads 
Bonaventure, P; Letavic, M; Dugovic, C; Wilson, S; Aluisio, L; Pudiak, C; Lord, B; Mazur, C; Kamme, F; Nishino, S; Carruthers, N; Lovenberg, T 
2007 
Yes 
Biochemical Pharmacology
ISSN: 0006-2952
EISSN: 1873-2968 
73 
8 
1084-1096 
English 
17129577 
The successful cloning and functional expression of the histamine H-3 receptor in the late 1990s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H-3 antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H-3 receptor. Analysis of structural features common to several series of non-imidazole H-3 receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H-3 antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H-3 antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H-3 antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H-3 antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H-3 antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders. (c) 2006 Elsevier Inc. All rights reserved. 
histamine H3 receptor; narcolepsy; cognition; JNJ-S207852; JNJ-10181457; modafinil-induced wakefulness; brain histamine; constitutive activity; pharmacological characterization; food-intake; mice; rat; ligands; cloning; neurons