Abstract
The human histamine H1 receptor (H1R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H1R by evaluating >130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H1R agonist (Mol Pharmacol65:538–549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H1R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.
Footnotes
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R.L. is a recipient of a PIONIER award of the Technology Foundation (Stichting Technische Wetenschappen) of the Netherlands Foundation of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.118869.
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ABBREVIATIONS: H1R, histamine H1 receptor; CNS, central nervous system; R-SAT, receptor selection and amplification technology; NF-κB, nuclear factor-κB; DS-121, S-(–)-3-(3-cyanophenyl)-N-n-propyl piperidine; JL-18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine; LY 53,857, 6-methyl-1-(methylethyl)-ergoline-8β-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate; MDL 10097, (±)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol]; MK 212, 6-chloro-2-(1-piperazinyl)pyrazine; SB 206553, 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole; SCH 12679, N-methyl-1-phenyl-7,8-dimethoxy-2,3,4,5-tetra-hydro-3-benzazepine maleate; SCH 23390, 7-chloro-8-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; SKF 38393, 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol; SKF 83566, (–)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine; mirtazepine [Org 3770; (±)-1,2,3,4,10,14b-hexahydro-2-methylpyrazino-[2,1-a]pyrido[2,3-c][2]benzazepine]; DMEM, Dulbecco's modified Eagle's medium; GPCR, G protein-coupled receptor.
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↵1 Current affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
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↵2 Current affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
- Received January 2, 2007.
- Accepted March 30, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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