A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors
| Autor: | Neepa Y. Choksi, Remko A. Bakker, Henk Timmerman, Rob Leurs, Raymond G. Booth, William B. Nix, Nader H. Moniri |
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| Přispěvatelé: | Medicinal chemistry, Chemistry and Pharmaceutical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
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Complementary Tetrahydronaphthalenes Stereochemistry Inositol Phosphates Mepyramine Guinea Pigs CHO Cells Biology Ligands Transfection Binding Competitive Histamine Agonists chemistry.chemical_compound Ileum Cricetinae Chlorocebus aethiops Phenylaminotetralin Radioligand medicine Animals Humans Inositol Receptors Histamine H1 Receptor Pharmacology Pyrilamine Phospholipase C Cell Membrane NF-kappa B Smooth muscle contraction chemistry Competitive antagonist Type C Phospholipases COS Cells Molecular Medicine Thermodynamics Radiopharmaceuticals SDG 6 - Clean Water and Sanitation medicine.drug Histamine |
| Zdroj: | Booth, R G, Moniri, N H, Bakker, R A, Choksi, N Y, Nix, W B, Timmerman, H & Leurs, R 2002, ' A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors ', The Journal of Pharmacology and Experimental Therapeutics, vol. 302, no. 1, pp. 328-36 . https://doi.org/10.1124/jpet.302.1.328 The Journal of Pharmacology and Experimental Therapeutics, 302(1), 328-36. American Society for Pharmacology and Experimental Therapeutics |
| ISSN: | 0022-3565 |
| DOI: | 10.1124/jpet.302.1.328 |
| Popis: | Previously, (−)- trans -1-phenyl-3- N , N -dimethylamino-1,2,3,4-tetrahydronaphthalene ([−]- trans -H 2 -PAT) was shown to activate stereospecifically histamine H 1 receptors coupled to modulation of tyrosine hydroxylase activity in guinea pig and rat forebrain in vitro and in vivo. Furthermore, the novel radioligand [ 3 H](−)- trans -H 2 -PAT was shown to label selectively H 1 receptors in guinea pig and rat brain with high affinity ( K D , ∼0.1 and 0.5 nM, respectively) and a B max about 50 and 15%, respectively, of that observed for the H 1 antagonist radioligand [ 3 H]mepyramine. In the current study, [ 3 H](−)- trans -H 2 -PAT-labeled cloned guinea pig and human H 1 receptors in Chinese hamster ovary (CHO) cell membranes with high affinity ( K D , ∼0.08 and 0.23 nM, respectively) and a B max about 15% of that observed for [ 3 H]mepyramine. The binding of H 2 -PAT to H 1 receptors in both CHO-H 1 cell lines was stereoselective with the (−)- trans -isomer having affinity ( K i , ∼1.5 nM) about 4-, 20-, and 50-times higher than the (−)- cis -, (+)- trans -, and (+)- cis -isomers, respectively; the affinity of (−)- trans -H 2 -PAT was unaffected by excess GTP. In functional assays, (−)- trans -H 2 -PAT was a full antagonist of histamine H 1 -mediated stimulation of phospholipase C (PLC) and [ 3 H]inositol phosphates (IP) formation in CHO-H 1 cells, a full inverse agonist of constitutively active H 1 receptors in COS-7-H 1 cells, and a full competitive antagonist (p A 2 = 9.2) of histamine H 1 -mediated contraction of guinea pig ileum. It is concluded that (−)- trans -H 2 -PAT is an antagonist at H 1 receptors coupled to PLC/IP formation and smooth muscle contraction. Meanwhile, the observation that [ 3 H](−)- trans -H 2 -PAT labels only a subpopulation of H 1 receptors and that (−)- trans -H 2 -PAT activates H 1 receptors coupled to modulation of tyrosine hydroxylase suggests that there may be post-translational H 1 receptor heterogeneity. |
| Databáze: | OpenAIRE |
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