P-Methylthioamphetamine Is a Potent New Non-Neurotoxic Serotonin-Releasing Agent

Journalof Pharmacology229, (1992)31-38 31 1992ElsevierSciencePublishersB.V.All rights reserved 0014-2999/92/$05.(10 '52790 p-Methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent Xuemei Huang, Danuta Marona-Lewicka and David E. Nichols Deportmentof Pharmacologandy Toxicologyand, Deportmentof M.edicinal_7_emisttyand Pharmacognosy,PurdueUnit'ersity, Schoolof PharmacyandPharmacalSciences,WestLaJ_tyetteIN, 47007,USA Received 14May I992, revised MS received 2 September 1992, accepted 8 September 1992 p-Methylthioamphetamine (MTA), was compared to p-chloroamphctamine (PCA) in a number of pharmacological assays. MTA was about 2-fold more potent than PCA at inhibiting synaptosomal uptake of [-_H}5-hydroxytryptamine ([3H]5-HT), and about 7-fold and 10-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]dopamine and [3H]norepinephrine, respectively. In drug discrimination assays, MTA was nearly equipotent to PCA in animals trained to discriminate saline from 3,4-methylenedioxymethamphctamine (MDMA), or two related analogues S-(+)-N-methyl-l-(l,3-benzodioxol-5-yl)-2-butanamine (S-MBDB) or 5-methoxy-6-methyl-2-aminoindan (MMAI). MTA caused dose-dependent increases of tritium cffiux from superfused rat frontal cortex slices preloaded with ['_H]5-HT. comparable to that induced by an equal molar concentration of PCA. Thc potential ncurotoxicity of MTA was examincd by measuring monoamine and metabolitc levels at one wcck following an acute dose. A 10 rog/kg dose of PCA caused a 70-90% decrease of cortical, hippocampal and striatal 5-HT and 5-hydoxyindoleacetic acid (5-HIAA) levels, while twice the molar dose of MTA (21.3 rog/kg) had m) effect. Thus. MTA is a potent, selective, semtonin releaser, apparently devoid of semtonin neurotoxic effects. This work also supports the idea that catecholamine systems may play a critical role in the neurotoxicity of PCA-Iike compounds. p-Chloroamphctaminc; p-Mcthylthioamphctaminc; Drug discrimination: Uptake inhibition; Supcrfusion: 5-ITT (5-hydroxytryptaminc, scrotonin); Ncurotoxicity; Brain sliccs 1.Introduction willnot onlygive a nccdcd safety factor for anypoten- tial clinical use of this type of compound but also will Substantial efforts in our laboratory over many years provide tools for studying the mechanisms of behavior have been made to undcrstand thc structure-activity and neurotoxic activity of these types of compounds. relationships of substituted amphetamines which exert Data from recent research in our laboratory and a variety of pharmacological actions. Amphetamine others have provided cvidencc that drug-induced 5-HT derivatives such as 3,4-methylenedioxymcthamphcta- release is important in the discriminative cue of mine(MDMA),andp-chloroamphetamine(PCA)cause MDMA-likc drugs (Obertender and Nichols. 1988: central serotonin neurotoxicity which is marked by Nichols et al., 1986; Schechter, 1988: Nichols and persistent reductions in brain 5-hydoxytryptamine (5- Oberlender, 1990; Nichols et al., in press). 5-Methoxy- HT), 5-HT uptake sites, and tryptophan hydroxylase 6-methyl-2-aminoindan (MMAI), which possesses a activity (e.g. Schmidt et al., 1986; Battaglia et al., 1987: more potent in vitro serotonergic effect than MDMA 1988; Fuller and Shoddy, 19741. This persistent reduc- and has almost no dopaminergic effect, fully substi- tion in serotonin markers seems to correlate with the tutes for MDMA and S-(+)-N-methyl-l-(l,3-benzodi- degeneration of certain serotonin axonal projections in oxol-5-yl)-2-butanamine (S-MBDB) in drug discrimina- brain (O'Hearn et al., 1988; Mamounas and Molliver, tion experiments (Johnson et al., 1991a). Recently, in 19881. Developing less neurotoxic MDMA and PCA our laboratory,, MMAI has been used as a training analogues which preserve desired behavioral effects drug in drug discrimination experiments because of its greater serotonergic specificity and decreased neurotoxic effects (Nichols et al., in press). Correspondence to: D.E. Nichols, Department of Medicinal Chem- istry and Pharmacognosy, School of Pharmacy and Pharmacal Sci- Recent work suggests that non-vesicular dopamine ences, Purdue University.West Lafayette. IN 470117.USA. Tel. I re[ease plays a very important role in drug-induced (3171-494-1461. fax I (3171-494-t1790. serotonergic toxicity of these drugs. Compounds such 32 as MMAI, 5,6-methylenedioxy-2-aminoindan (MDAI), [3H]5-HT, [3H]dopamine and [3H]norepinephrine Were forc MBDB and 1-(4-chlorophenyl)-2-aminobutane (CAB) purchased from Amersham (Arlington Heights, IL) at pro[ which have little dopaminergic effect produce little or a specific activity. of l_J,o _ 5 and 13.8 Ci/mmol respe e- ,A no serotonergic toxicity (Johnson et al. 1990; 1991a; tively. (+)-Amphetamine sulfate was purchased fronal men Nash and Nichols, 1991; Nash and Brodkin, 1991). Smith Kline & French Laboratories (Philadelphia, PA). para Serotonin neurotoxicity induced by the combination of MDMA, S-MBDB, MMAI, as their hydrochlorides, deta the non-neurotoxic MDMA analogs MDAI or MMAI and LSD tartrate were synthesized in our laboratory Nict and the dopamine releasing agent (+)-amphetamine (Nichols et al., 1986; Johnson et al., 1991). With the the (Johnson and Nichols. 1991; Johnson et al., 1991b) exception of drug discrimination experiments, all drugs and gives additional strong support to the hypothesis of were injected subcutaneously. In drug discriminatio] tionl dopamine involvement in the serotonin neurotoxicity experiments, all drugs were dissolved in 0.9% salin_ were induced by these types of drugs, and were injected intraperitoneally in a volume of 1 sessi Based in part on the above studies, further explo- ml/kg. 30 min before the session. 85% ration of newMDMAand PCAanalogswithincreased pres serotonergic effects and/or decreased dopaminergic 2.2. Animals sion_ effects (i.e. highlyselectiveserotonergicagents!was sessi warranted. Most monoaminereleasingamphetamine eitht derivatives arc 3.4-disubstitutcd compounds ,c.g. Male Sprague-Dawley rats (Harlan. Indianapolis, and IN) welching I"q-9(}(I _ were used in all experiments. MDMA} or arc simpb monosubsitutcd at thc >ara _ " - -" Rat.' position. For thc latter, small electroneaativc groups .Animals were either group housed six per cage or spot - individually caged in a temperature controlled room - - testc such as mcthoxv, and chloro or other halogens eivc with a 12/12 h lighting schedule. With the exception of neurotoxiccompounds.It should be noted however, disC_ that thc halogens other than chlorine and bromine give rats used in the drug discrimination experiments, food achic compounds that arc less neurotoxic (Fuller et al.. 1975; and water were available ad libitum at all times. In sessi 1980). Thus. we reasoned that a larger, less electroneg- drug discrimination experiments. 62 male rats were to tl_ ativc group would be an interesting candidate. In par- used as subjects and divided into five groups (N = 9-15 of e ticular, a sulfur atom substitution seemed an appropri- per group), trained to discriminate MDMA (1.75 chan ate choice. Sulfur is hydrophobic, in thc same family of mg/kg). S-MBDB (1.75 mg/kg). MMAI (1.71 mg/kg), 50 P the periodic table as oxy.gen, and much less electroneg- ( + )-amphetamine (1.0 mg/kg) or LSD (0.08 mg/kg) rain, ativc than oxygen or chlorine. Following this reasoning, from saline. None of the rats had previously received Trea p-methylthioamphetamine (MTA). was synthesized in drugs or behavioral training. Water was freely available stud, our laboratory. This report discusses the pharmacology, in the home cages and a sufficient amount of supple- of MTA in a number of assays. The structures of PCA mental feeding (Purina, Lab Blox) was made available 2.4.. and MTA are shown in fig. 1. after experimental sessions so as to maintain them at neph As a simple screening procedure, the ability of MTA approximately 80% of free feeding weight, compared to substitute for MDMA, S-MBDB, MMAI. ( ?)- with control rats housed under the same conditions. In A neurochemical studies, rats were killed by decapitation, inamphetaminea drug discriminationand ( + )-lysergicparadigmacid diethylamidewas first (LSD)deter- the brains were removed and rapidly dissected on ice hom,emp] according to the procedure of Glowinski and Iversen usinl mined. Synaptosomal monoamine uptake inhibition ex- (1966). In neurotoxicity studies, the frontal cortex, hip- perimentswere thenusedto assessthe relativepotency horn, of the new compound to affect serotonin, dopamine, pocampus and striatum were frozen with liquid nitro- 4oc. and norepinephrine uptake and release. Superfusion gen. The samples were stored separately at -70°C Xg experiments were utilized to test its serotonin releasing until assay using HPLC-EC methods, pend properties. Finally,the abilityof the compoundto batio cause long-term depletion of monoamines in differenI 2.3. Drug discrimination an a rat brain regions(frontal cortex, hippocampusand meas striatum) was determined. Six standard operant chambers (Coulbourn Instru- respt ments, Lehigh Valley, PA) consisted of modular test addi: cages enclosed within sound-attenuated cubicles with tube_ 2. Materials and methods fans for ventilation and background white noise. A Hen: white house light was centered near the top of the 1.2 I_ 2.1. Materials front panel of the cage, which was also equipped with ascm two response levers, separated by a food hopper, all solut MTA and PCA were synthesized in our laboratory positioned 2.5 cm above the floor. Solid state logic in COne, using standard

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