Subject(s)
Histamine Agonists , Protein Structure, Tertiary , Receptors, Histamine H3 , Animals , Cell Line , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Histamine Agonists/chemistry , Histamine Agonists/metabolism , Humans , Imidazoles/chemistry , Imidazoles/metabolism , Ligands , Rats , Receptors, Histamine H3/chemistry , Receptors, Histamine H3/metabolismSubject(s)
Alkaloids , Histamine Antagonists , Receptors, Histamine H3/metabolism , Alkaloids/chemistry , Alkaloids/metabolism , Animals , Dose-Response Relationship, Drug , Drug Design , Guanosine Triphosphate/metabolism , Histamine Agonists/metabolism , Histamine Antagonists/chemistry , Histamine Antagonists/metabolism , Humans , Male , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
Although the histamine H(3) receptor was identified pharmacologically in 1983, and despite widespread pharmaceutical interest in the target, no compound interacting specifically with this site has undergone successful clinical examination to develop the necessary proof-of-concept data. Therefore, clinical knowledge of the therapeutic potential of H(3) receptor antagonists in neuropsychiatric diseases, in metabolic diseases or in sleep disorders has yet to determine if the preclinical data that show broad efficacy in animal models of the aforementioned states are relevant to current unmet medical needs. H(3) receptors are complex, with species-related sequence differences that impact pharmacological responses. The receptors have a complex gene organization that provides opportunity for multiple slice isoforms, most of which remain poorly characterized even within a species. H(3) receptors are constitutively active, although the extent of this could vary either between species and/or receptor splice isoforms, both of which may provide opportunity for preferential coupling to different G-proteins. Thus, it is not surprising that the pharmacological effects of known H(3) ligands are complex and diverse, since these agents may act both as agonists and antagonists in different systems. Moreover, other compounds show inverse agonism in some models but neutral antagonist activity in others. Some of this diversity may be related to different ligand-dependent receptor activation states or to the effects of key amino acids important for ligand recognition. This commentary provides an overview of these complexities as applied to the H(3) receptor and the challenges these intricacies create for drug discovery.
Subject(s)
Drug Design , Histamine Agonists , Histamine Antagonists , Receptors, G-Protein-Coupled , Receptors, Histamine H3/metabolism , Animals , Drug Evaluation, Preclinical , Histamine Agonists/adverse effects , Histamine Agonists/chemistry , Histamine Agonists/pharmacology , Histamine Antagonists/adverse effects , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Humans , Ligands , Molecular Structure , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/physiology , SafetyABSTRACT
Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology.