ABSTRACT
The histamine H3 receptor (H3R) was first characterized, in 1983, as a presynaptic autoreceptor controlling histamine release in the brain using existing H1 and H2 antagonists as probes in a classical pharmacological approach. A high constitutive activity of this receptor coupled with the fact that its ligands displayed protean agonism as well as a lot of pharmacological heterogeneity found among various species and the human receptors complicated the H3R pharmacology. In the late 1990s, two major breakthroughs occurred to reignite the H3 field. First, the human H3R was cloned, allowing the detailed investigation of H3 pharmacology in a homogenous system and the initiation of several high-throughput screening efforts. Second, nonimidazole-based antagonists were discovered, providing the opportunity to circumvent the suboptimal properties of first-generation imidazole-based H3 antagonists. Various nonimidazole H3R ligands were then developed by efforts of various pharmaceutical companies and academic research groups.
