A Novel Phenylaminotetralin Radioligand Reveals a Subpopulation of Histamine H1 Receptors

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Abstract
Previously, (−)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene ([−]-trans-H2-PAT) was shown to activate stereospecifically histamine H1 receptors coupled to modulation of tyrosine hydroxylase activity in guinea pig and rat forebrain in vitro and in vivo. Furthermore, the novel radioligand [3H](−)-trans-H2-PAT was shown to label selectively H1 receptors in guinea pig and rat brain with high affinity (KD, ∼0.1 and 0.5 nM, respectively) and a Bmax about 50 and 15%, respectively, of that observed for the H1antagonist radioligand [3H]mepyramine. In the current study, [3H](−)-trans-H2-PAT-labeled cloned guinea pig and human H1 receptors in Chinese hamster ovary (CHO) cell membranes with high affinity (KD, ∼0.08 and 0.23 nM, respectively) and a Bmax about 15% of that observed for [3H]mepyramine. The binding of H2-PAT to H1 receptors in both CHO-H1 cell lines was stereoselective with the (−)-trans-isomer having affinity (Ki, ∼1.5 nM) about 4-, 20-, and 50-times higher than the (−)-cis-, (+)-trans-, and (+)-cis-isomers, respectively; the affinity of (−)-trans-H2-PAT was unaffected by excess GTP. In functional assays, (−)-trans-H2-PAT was a full antagonist of histamine H1-mediated stimulation of phospholipase C (PLC) and [3H]inositol phosphates (IP) formation in CHO-H1 cells, a full inverse agonist of constitutively active H1 receptors in COS-7-H1cells, and a full competitive antagonist (pA2 = 9.2) of histamine H1-mediated contraction of guinea pig ileum. It is concluded that (−)-trans-H2-PAT is an antagonist at H1 receptors coupled to PLC/IP formation and smooth muscle contraction. Meanwhile, the observation that [3H](−)-trans-H2-PAT labels only a subpopulation of H1 receptors and that (−)-trans-H2-PAT activates H1receptors coupled to modulation of tyrosine hydroxylase suggests that there may be post-translational H1 receptor heterogeneity.

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