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2328 Biol. Pharm. Bull. 30(12) 2328—2333 (2007) Vol. 30, No. 12 In Vitro Screening of Psychoactive Drugs by [35S]GTPgS Binding in Rat Brain Membranes ,a b a a Ryouichi NONAKA,* Fumiko NAGAI, Akio OGATA, and Kanako SATOH a Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health; 3–24–1 Hyakunincho, Shinjuku-ku, Tokyo 169–0073, Japan: and b Pharmaceutical Safety Guide section, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government; 2–8–1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 163–8001, Japan. Received June 26, 2007; accepted October 5, 2007; published online October 9, 2007 We constructed a reproducible, simple, and small-scale determination method of the psychoactive drugs -(that acted directly on the monoamine receptor by measuring the activation of [35S]guanosine-5؅-O-(3-thio triphosphate binding to guanine nucleotide-binding proteins (G proteins). This method can simultaneously measure the effects of three monoamines, namely dopamine (DA), serotonin (5-HT), and norepinephrine (NE), in rat brain membranes using a 96-well microplate. Activation of D1 and D2 receptors in striatal membranes by DA as well as 5-HT and NEa2 receptors in cortical membranes could be measured. Of 12 tested phenethylamines, 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,5-dimethoxy-4-ethylphenethylamine (2C-E), and 2,5-dimethoxy- 4-iodophenethylamine (2C-I) stimulated G protein binding. The other phenethylamines did not affect G protein binding. All 7 tryptamines tested stimulated G protein binding with the following rank order of potency; 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT)Ͼ5-methoxy-N,N-diallyltryptamine (5-MeO-DALT)Ͼ5-methoxy- a-methyltryptamine (5-MeO-AMT)Ն5-methoxy-N,N-methylisopropyltryptamine (5-MeO-MIPT)Ͼ5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT)ϾN,N-dipropyltryptamine (DPT)Նa-methyltryptamine (AMT). This assay system was able to designate psychoactive drugs as prohibited substances in accordance with criteria set forth by the Tokyo Metropolitan government. Key words G protein binding; monoamine; dopamine; serotonin; norepinephrine; psychoactive drug In today’s world including Japan, non-prescription psy- (for example, 3,4,5-trimethoxyamphetamine (TMA), 2,4,5- choactive drugs are widely used by many people, particularly trimethoxyamphetamine (TMA-2), and 2,4,6-trimethoxyam- by the young. These drugs have been synthesized by minor phetamine (TMA-6)) reveal no presynaptic effects, it is modifications to the chemical structures of existing drugs reported that these drugs elicit hallucinogenic effects in and are called designer drug. For example, methylene- human.5) Thus, it is also possible that these designer drugs dioxymethamphetamine (MDMA) was derived from amphet- could modify brain activity by directly interacting with amine by altering the natural molecular structure.1) Although monoamine receptors. Many monoamine receptors, includ- the use of MDMA is prohibited in many countries, new psy- ing DA, 5-HT, and NE receptors belong to the superfamily choactive chemicals are being constantly developed and can of seven-transmembrane-domain, guanine nucleotide-bind- be easily obtained from individuals or via the Internet. The ing protein (G protein)-coupled receptors.6) G protein-cou- Tokyo Metropolitan Government in Japan enacted an “Ordi- pled receptors play a crucial role in regulating physiological nance concerning the abuse prevention of the psychoactive functions, and consequently are targets for the action of drugs” in April 2006 that prohibited the manufacture, culti- many classes of drugs. Because the [35S]guanosine-5Ј-O-(3- vation, sales, possession, use, etc., of these drugs. Therefore, thio)-triphosphate ([35S]GTPgS) binding assay is thought to we are developing screening methods to rapidly elucidate the be a relatively simple functional assay of receptor-mediated effects of these drugs on the central nervous system. G protein activation,7) we tried to construct a simple and Psychoactive drugs are roughly classified into phenethyl- small-scale method for determining G protein binding using amine, tryptamine, and piperazine derivatives. Many of the the rat brain membranes. psychoactive drugs modify the monoamine neurotransmis- sion systems including the dopaminergic, serotonergic, and MATERIALS AND METHODS adrenergic neuronal systems.2,3) We previously constructed a reproducible, simple, and small-scale in vitro determination Chemicals Psychoactive chemicals were purchased from method for the reuptake and release of monoamines (dopamine adult goods shops in Tokyo (Table 1). The structures of the (DA), serotonin (5-HT), and norepinephrine (NE)) using rat drugs are shown in Fig. 1. The purity of the drugs was deter- brain membranes. This method was then applied to study the mined by HPLC (Alliance PDA system, Waters Co., MA, effects of designer drugs on monoamine reuptake and re- U.S.A.) with L-column ODS, 5 mm, 4.6ϫ150 mm (Chemi- lease. We have been investigating the effects of 21 designer cals Evaluation and Research Institute, Japan) and a solvent 8) drugs, some of which are known to be psychoactive in man. of H2O/acetonitrile/phosphoric acid/SDS (580/420/1/12.5 g). For example, 4-fluoroamphetamine (4-FMP), 1-(1,3-benzodi- Drugs were dissolved in dimethylsulfoxide (DMSO) for the oxol-5-yl)-2-butanamine (BDB), 2-methylamino-3,4-methyl- GTP binding assay. [35S]GTPgS (46.25 TBq/mmol) was enedioxy-propiophenone (methylone), and a-methyltrypta- purchased from Perkin Elmer Co., Ltd. (MO, U.S.A.). DA, 5- mine (AMT) showed strong reuptake inhibition and release HT, NE, guanosine 5Ј-diphosphate (GDP), 8-cyclopentyl- acceleration of DA, 5-HT, and NE.4) 1,3-dipropylxanthine (DPCPX), SCH23390, sulpiride, me- Although many of drugs described in our previous report4) thiothepin, WAY100635, SB224289, propranolol, and yohim- ∗ To whom correspondence should be addressed. e-mail: [email protected] © 2007 Pharmaceutical Society of Japan December 2007 2329 Table1. Psychoactive Drugs Characteristics No. Drugs Abbreviations Purity (%) Phenethylamines 1 3,4-Methylenedioxymethamphetamine MDMA 98.0 2 2-Methylamino-3,4-methylenedioxy-propiophenone Methylone 98.8 3 1-(1,3-Benzodioxol-5-yl)-2-butanamine BDB 97.1 4 N-Methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine MBDB 99 5 2,5-Dimethoxy-4-chlorophenethylamine 2C-C 94.2 6 2,5-Dimethoxy-4-ethylphenethylamine 2C-E 100 7 2,5-Dimethoxy-4-iodophenethylamine 2C-I 99.1 8 3,4,5-Trimethoxyamphetamine TMA 99.3 9 2,4,5-Trimethoxyamphetamine TMA-2 98.6 10 2,4,6-Trimethoxyamphetamine TMA-6 98.1 11 2-Fluoroamphetamine 2FMP Ͼ98.0 12 3-Fluoroamphetamine 3FMP Ͼ98 13 4-Fluoroamphetamine 4FMP Ͼ98 Tryptamines 14 a-Methyltryptamine AMT 99.0 15 5-Methoxy-a-methyltryptamine 5-MeO-AMT 92.7 16 N,N-Dipropyltryptamine DPT 96.9 17 5-Methoxy-N,N-diisopropyltryptamine 5-MeO-DIPT 96.1 18 5-Methoxy-N,N-methylisopropyltryptamine 5-MeO-MIPT 99.5 19 5-Methoxy-N,N-dimethyltryptamine 5-MeO-DMT 91.7 20 5-Methoxy-N,N-diallyltryptamine 5-MeO-DALT 87.8 Piperazines 21 1-(3-Chlorophenyl)piperazine 3CPP 98.0 22 1-(4-Methoxyphenyl)piperazine 4MPP 90.0 23 1-Benzylpiperazine BZP 98.0 The purities were obtained by HPLC.8) Fig. 1. Structures of the Designer Drugs 2330 Vol. 30, No. 12 bine were obtained from Sigma-Aldrich (MO, U.S.A.). ing values for 0.1% DMSO from stimulated values (obtained Saponin was purchased from Calbiochem Co., Ltd. (La Jolla, in the presence of monoamines or drugs). The EC50 values U.S.A.). Other reagents used in the study were of the highest were calculated as the concentrations required to elicit G pro- grade commercially available. Lumasafe Plus, the scintilla- tein activation equal to half of the maximum effect. The % tion cocktail, was purchased from Lumac. Lsc B. V. (Gronin- Emax values represented the percent maximal increase in the gen, The Netherlands). binding above basal binding. The % of 5-HT maxima was Animals Male Sprague Dawley rats (Crl:CD(SD):300— determined by dividing NE- or drug-induced maximal bind- 400 g) were obtained from Charles River Japan (Kanagawa, ing by the 5-HT-stimulated maximal binding value which Japan) and were housed in a room at 22—24 °C, 45—65% was as a reference. humidity with 12 h-light and 12 h-dark cycles. Water and Statistical Analysis EC50 values were determined using food were supplied ad libitum. All procedures involving ani- the sigmoidal dose-response curve fitting function of Kalei- mals were approved by the institutional animal care and use daGraph ver. 4 software (Synergy Software, PA, U.S.A.). The committee and conform to the guidelines in The UFAW data represented the mean values of three independent exper- Handbook on the Care and Management of Laboratory Ani- iments (nϭ3). mals. Membrane Preparation Male SD rats were killed by RESULTS decapitation under ether anesthesia and their brains were quickly removed. Membranes were prepared according to Pharmacological Properties of [35S]GTPgS Binding methods reported by Breivogel et al..9) The cerebral cortex of Brain Membranes Drug-stimulated G protein binding and striatum were dissected on ice and homogenized in 25 was successfully determined using the saponin-treated brain volumes of ice-cold HEPES buffer (pH 7.6, 20 mM HEPES, membranes (data not shown). We optimized the sensitivity of 7mM MgCl2, 100 mM NaCl, 1 mM EDTA, 0.2 mM dithiothre- the assay system for screening the GTP-binding assay in- itol (DTT)) by 20 strokes with a Teflon-glass homogenizer. duced by DA, 5-HT, and NE. The optimal assay conditions All subsequent centrifuge procedures were carried out at (reaction time and temperature, DPCPX content in the reac- 4°C. Following centrifugation of the homogenate at 800ϫg tion mixture, protein concentration of brain membranes; data for 10 min, the supernatant was homogenized with a Polytron not shown) are described in the Materials and Methods.
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    Abbreviations and chemical names of compounds not defined in the text [3H]CP-55: 940, 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol; 18F-DOPA: 18F-fluoro-L-dihydroxyphenylalanine; 25C-NBOME: 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2 methoxyphenyl)methyl]ethanamine; 25I-NBOME: 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine; 2C-B: 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine; 4-HO-DALT: 3-{2-[di(prop-2-en-1-yl)amino]ethyl}-1H-indol-4-ol; 5F-ADBINACA: (1-(5-fluoro-pentyl)-1H-indole-3-carboxylic acid (1-carbamoyl-2-methyl-propyl)-amide; 5F-AKB-48: N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3-carboxamide; 5F-PB-22: 1-pentyfluoro-1H-indole-3-carboxylic acid 8-quinolinyl ester; 5F-SDB-005: 1-(5-Fluoropentyl)-N-phenyl-1H-indole-3-carboxamide; 5-MeO-AMT: 5-methoxy-α-methyltryptamine; 5-MeO-DALT: N-allyl-N-[2-(5-methoxy-1H-indol-3-yl)ethyl] prop-2-en-1- amine; AB-FUBINACA: N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indazole‐3‐carboxamide; AB-PINACA: (S)-N-(1-Amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-inda-zole-3-carboxamide; ADB-FUBINACA: (S)-N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluoroben-zyl)-1H-indazole-3-carboxamide; AKB-48: N-(1-Adamantyl)-1-pentylindazole-3-carboxamide; AM 251: N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AMB-FUBINACA: methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate; AMT: α-methyltryptamine; BB-22: 1-(cyclohexylmethyl)-1H-indole-3-carboxylic acid 8-quinolinyl ester; Bromo-DragonFly: 1-(4-Bromofuro[2,3-f]