Since the histamine-3 receptor (H3R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H3R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H3R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H3R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H3R field, together with a brief overview of the clinical trials currently running.
Keywords: Obesity, metabolic diseases, histamine-3, inverse agonist, protean agonist, safety, pharmacophore model, clinical trials, H3R, complex, dichotomy in efficacy, prevalence of obesity, Thrifty Genes Hypothesis, fat mass, hyperglycemia
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