A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors.
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Booth RG, Moniri NH, Bakker RA, Choksi NY, Nix WB, Timmerman H, Leurs R
A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors.
J Pharmacol Exp Ther. 2002 Jul;302(1):328-36.
- PubMed ID
- 12065734 [ View in PubMed]
- Abstract
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 (pA(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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Chlorpheniramine Histamine H1 receptor Ki (nM) 4.81 N/A N/A Details Chlorpheniramine Histamine H1 receptor Ki (nM) 2.67 N/A N/A Details Clozapine Histamine H1 receptor Ki (nM) 1.63 N/A N/A Details Clozapine Histamine H1 receptor Ki (nM) 1.54 N/A N/A Details Diphenhydramine Histamine H1 receptor Ki (nM) 13.5 N/A N/A Details Diphenhydramine Histamine H1 receptor Ki (nM) 11.7 N/A N/A Details Doxepin Histamine H1 receptor Ki (nM) 0.32 N/A N/A Details Doxepin Histamine H1 receptor Ki (nM) 0.09 N/A N/A Details Mepyramine Histamine H1 receptor Ki (nM) 1.18 N/A N/A Details Mepyramine Histamine H1 receptor Ki (nM) 1.01 N/A N/A Details Triprolidine Histamine H1 receptor Ki (nM) 1.53 N/A N/A Details Triprolidine Histamine H1 receptor Ki (nM) 1.11 N/A N/A Details