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In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists

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In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs As Inverse H1 Receptor Agonists 0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles. We have used the cell-based receptor selection H1R inverse agonist activity. Absolute and rank order of func- and amplification technology assay to further define the clinical tional potency of these clinically relevant brain-penetrating Ͼ pharmacology of the human H1R by evaluating 130 therapeu- drugs may possibly be used to predict aspects of their clinical tic and reference drugs for functional receptor activity. Based profiles, including propensity for sedation. at ASPET Journals on March 10, 2015 Antagonists of the histamine H1 receptor (H1R) have though many of the first generation antihistamines exhibit proven effective in controlling many of the symptoms of the additional anticholinergic properties that may contribute to human allergic response. Classical H1R antagonists, known their sedative properties, selective H1R antagonists acting in as “first generation” antihistamines, may act as sedatives the CNS might be exploited as sleeping aids. Subsequent upon crossing the blood-brain barrier, interacting with H Rs 1 development of antihistamines focused on H1R antagonists expressed in the central nervous system (CNS). Moreover, that do not cross the blood-brain barrier, resulting in what sedation and performance impairment are undesirable and are now termed “second generation” antihistamines (Zhang potentially dangerous side effects of first generation antihis- et al., 1997). Another advantage of these second-generation tamines, and they are a major limitation of their use. Al- antihistamines is their increased selectivity for H1Rs over other related monoaminergic receptor subtypes (Walsh et al., R.L. is a recipient of a PIONIER award of the Technology Foundation 2001). In contrast to second generation antihistamines, com- (Stichting Technische Wetenschappen) of the Netherlands Foundation of Sci- entific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek). pounds developed to treat neuropsychiatric disease are spe- 1 Current affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, cifically designed to enter the CNS and target various mono- Biberach, Germany. 2 Current affiliation: University of North Carolina at Chapel Hill, Chapel aminergic G protein-coupled receptors and small molecule Hill, North Carolina. reuptake transporters. Radioligand binding studies have Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. demonstrated that these compounds lack target specificity doi:10.1124/jpet.106.118869. and that they may act at multiple receptor and transporter ␬ ABBREVIATIONS: H1R, histamine H1 receptor; CNS, central nervous system; R-SAT, receptor selection and amplification technology; NF- B, nuclear factor-␬B; DS-121, S-(Ϫ)-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-8␤-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate; MDL 10097, (Ϯ)-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, (Ϫ)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine; mirtazepine [Org 3770; (Ϯ)-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. 172 Pharmacology of CNS-Active Drugs as Inverse H1R Agonists 173 sites simultaneously (Hill and Young, 1978; Richelson, 1978; astemizole (Janssen Pharmaceutica NV, Beerse, Belgium), cypro- Richelson and Nelson, 1984a; Cusack et al., 1994; Richelson heptadine hydrochloride (MSD, Haarlem, The Netherlands), d-chlor- and Souder, 2000). It is noteworthy that many of these com- pheniramine maleate (A. Beld, Nijmegen, The Netherlands), diphen- hydramine hydrochloride (Gist-Brocades, Delft, The Netherlands), pounds have been shown to possess high H1R affinity (Tran et al., 1978; Richelson and Nelson, 1984a; Bymaster et al., levocabastine (Janssen Pharmaceutica NV), loratadine (Schering 1996; Richelson and Souder, 2000). Examples of such mole- Plough, Bloomfield, NJ), mainserin hydrochloride and mirtazepine (Organon NV, Oss, The Netherlands), pcDEF (Dr. J. Langer, Robert cules include antipsychotic drugs such as clozapine and tri- 3 Wood Johnson Medical School, Piscataway, NJ), and ranitidine di- cyclic antidepressant drugs such as amitriptyline. Because hydrochloride (GlaxoSmithKline, Uxbridge, Middlesex, UK), and of interactions with H1Rs in brain can produce clinically signif- the cDNA encoding the human histamine H1R (Fukui et al., 1994) icant adverse effects, including sedation (Sekine et al., 1999; are greatly acknowledged. Bakker et al., 2002; Simons, 2002), and possibly alterations Molecular Cloning. The genes coding for the human H1R and ␣ in body weight (Kroeze et al., 2003; Roth and Kroeze, 2006), the G q subunit were cloned as described previously (Burstein et al., an improved understanding of the full extent of the H1R- 1995; Bakker et al., 2004). All receptor and G protein constructs were mediated actions of neuropsychiatric drugs as a class may fully sequence-verified by dideoxy chain termination methods. The provide critical insight into their clinical profiles. sequence of the human H1R used in this study corresponds to Gen- Drugs with antihistaminergic activity have been tradition- Bank accession no. D14436. All plasmid DNA used for transfections ally classified as pharmacological antagonists of histamine at was prepared using resin-based mega-prep purifications following the manufacturer’s protocol (QIAGEN GmbH). the H1R, acting by competitively binding to the receptor, Downloaded from thereby blocking H R-mediated responses (Hill et al., 1997; Cell Culture and Transfection. COS-7 African green monkey 1 kidney cells were maintained at 37°C in a humidified 5% CO , 95% Zhang et al., 1997). However, the techniques previously used 2 air atmosphere in Dulbecco’s modified Eagle’s medium (DMEM) to assess H R activity of commonly used therapeutics lack 1 containing 2 mM L-glutamine, 50 IU/ml penicillin, 50 ␮g/ml strepto- the ability to discriminate the functional nature of these mycin, and 5% (v/v) fetal calf serum. COS-7 cells were transiently interactions. More recent studies, using functional assays, transfected using the DEAE-dextran method as described previously have shown that some antihistamines possess negative in- (Bakker et al., 2001). The total amount of DNA transfected was jpet.aspetjournals.org trinsic activity at the H1R, which has led to the reclassifica- maintained constant by addition of pcDEF3. NIH-3T3 cells were tion of these agents as H1R inverse agonists (Weiner et al., cultured in DMEM supplemented with 2 mM L-glutamine, 1% pen- 1999; Bakker et al., 2000, 2001). These observations raise icillin and streptomycin, and 10% bovine calf serum and maintained important questions as to the critical physiological role of at 37°C in a humidified 5% CO2, 95% air atmosphere. NIH-3T3 cells were transiently transfected using the SuperFect transfection re- basal H1R signaling and potential pharmacological impor- tance of negative intrinsic versus neutral antagonistic activ- agent (QIAGEN GmbH) following the manufacturer’s protocol. ity of the multitude of clinically useful compounds that in- R-SAT Assays. R-SAT assays were performed as described pre- viously (Weiner et al., 2001; Bakker et al., 2004). On forming a at ASPET Journals on March 10, 2015 teract with H Rs. 1 monolayer, NIH-3T3 cells normally stop growing due to contact We have used the cell-based functional assay receptor se- inhibition. In R-SAT assays, the activation of pathways, i.e., through lection and amplification technology (R-SAT) to further ex- the activation of GPCRs, that promote cell growth result in NIH-3T3 plore the clinical pharmacology of a variety of CNS drugs as cells being able to overcome their contact inhibition and proliferate. inverse agonists at the human H1R. We demonstrate a strong These stimulatory effects can be readily quantified using a marker correlation between the affinity of known histaminergic gene, which allows graded responses to be measured, permitting drugs at the H1R, as determined by radioligand binding, and precise determinations of ligand potency and efficacy.
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