The histamine H3 receptor (H3R) is a G-protein coupled receptor localized principally in the CNS that plays a role in cognitive and homeostatic control, including appetitive behavior. Targeted disruption of H3R in mice leads to an obese phe-notype, including increased weight, food intake, adiposity, and reduced energy expenditure . Some potent H3R antagonists have been reported to decrease food intake, but show minimal activity in other CNS models. Other antagonists have shown efficacy in CNS models, but not obesity models. The reasons for this discrepancy are not known, but may be due to different splice variants in the hypothalamus versus the other areas of the brain. Several recent reviews describe in more detail some of the other reasons for the varying activities of H3 antagonists in obesity versus CNS models [106,107].
A piperazine derivative 53 (NNC 38-1049) was recently described as a potent H3R competitive antagonist [hKb = 2.3 nM (cAMP assay), rK; = 5 nM (GTP-g-35S assay)]. This compound was brain penetrant, with hypothalamic exposure of 3000 ng/g tissue following a 60 mg/kg oral dose . It was also shown to increase histamine levels in the PVN, which has a large population of H1R and H3R and is the likely site of action for the anti-obesity effects. Oral administration of 53 to DIO rats resulted in a reduction of food intake and a significant decrease in body weight. No changes were observed in the behavioral satiety sequence or in pica consumption following intraperitoneal administration.
The biphenyl derivative 54 (A-423579, hH3R pK = 8.69, rH3R pK = 8.27) has been shown to cause weight loss in rodent models . Compound 54 exhibited both antagonist and inverse agonist activities (GTP-g-35S inverse agon-ism pEC50 = 7.71). This pyrrolidine derivative was efficacious in DIO rats following oral administration. Weight loss with 54 was gradual and cumulative, unlike that observed for the positive control in the study, sibutramine, which diminished over time. Compound 54 did not decrease food intake in H3R KO mice . The des-fluoro analog 55 was equipotent to 54 in a binding assay, but was found to have genetic toxicology issues . As previously noted for compounds that target H3R, 54 was efficacious only in anti-obesity models - it did not show any significant activity in an inhibitory avoidance model that was developed to characterize the attentional and cognitive effects of H3R antagonists .
Many new H3R chemotypes have been reported in the patent application literature in the past year. However it is not clear which compounds may be useful as weight-loss agents or as agents to treat CNS indications such as attention-deficit hyperactivity disorder (ADHD). Several reviews describe new H3R antagonists that have recently been disclosed [106,107].
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