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CELLULAR AND MOLECULAR

G Protein-Dependent Pharmacology of Histamine H₃ Receptor Ligands: Evidence for Heterogeneous Active State Receptor Conformations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Previously reported pharmacological studies using the imidazole-containing histamine H₃ receptor ligands GT-2331 (Cipralisant) and proxyfan resulted in a range of classifications (antagonist, agonist, and protean) for these compounds. We examined the role that the signaling system, with particular emphasis on the type of G protein, had on the pharmacology observed for H₃ ligands. Ligands were assessed using assays measuring neurotransmitter release, cAMP, and guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding. Whereas clobenpropit and ciproxifan were consistently antagonists, GT-2331, proxyfan, and imetit exhibited differential activity. Although GT-2331 and proxyfan exhibited little agonist activity in neurotransmitter release assays, both demonstrated full agonism relative to (R)--methylhistamine in cAMP assays. In [³⁵S]GTPS binding assays, GT-2331 and proxyfan demonstrated partial agonism. Imetit showed full agonism in most assays, but it was slightly less efficacious in a neurotransmitter release assay and in [³⁵S]GTPS binding at the human H₃ receptor. To further examine these ligands, we coexpressed G16 or chimeric Gq/i₅ in human embryonic kidney cells expressing the human H₃ receptor and assayed intracellular calcium and cAMP levels. GT-2331, proxyfan, and imetit demonstrated full agonism in all assays of cAMP activity. However, in cells expressing G16, they exhibited minimal agonism in calcium mobilization assays, whereas imetit showed partial agonism. When Gq/i₅ was used, the activity of both GT-2331 and proxyfan increased, whereas imetit became a full agonist. These results demonstrate that GT-2331 and proxyfan's differential pharmacology at the H₃ receptor depends on the type of G protein used and provide indirect evidence for differential ligand-bound active states that mediate signaling by the H₃ receptor.

Address correspondence to: Dr. Kathleen M. Krueger, Neurosciences Research, Abbott Laboratories, Department R4MN, Bldg. AP9A/319, 100 Abbott Park Rd., Abbott Park, IL 60064-6125. E-mail: kathleen.m.krueger{at}abbott.com

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