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1.
Addict Biol ; 12(1): 69-80, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17407499

ABSTRACT

Repeated administration of beta-phenylalkylamines is known to produce neuronal changes in the central and peripheral nervous systems of mammals. It is suggested that various components of the cytoskeleton undergo profound alterations after amphetamine use and misuse, contributing to behavioral changes and neurotoxicity. Here we studied the expression of microtubule-associated protein 2 (MAP2) and beta-actin after repeated intraperitoneal applications with equimolar doses of p-chloroamphetamine (PCA), methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) in the brain of male Wistar rats. Effective (molecular) pharmacological doses (ED) were derived and used for the calculation of (molecular) pharmacological indices (PI). Besides clear but different dose-response curves on the toxicity of the drugs, in situ hybridization and Western blot analysis revealed that repeated administration of these compounds resulted in different substance- and dose-dependent changes in MAP2 gene expression, e.g. in the frontoparietal somatosensoric cortex. In contrast, the expression of beta-actin was not influenced by any of the compounds at the dose levels tested. Lethal doses were determined with 2.1 (PCA), >5.1 (METH) and 8.4 mg/kg/day (MDMA). Linear and non-linear repeat-dose lethality was observed for MDMA and PCA, respectively, whereas METH was non-lethal in the dose range used. Values for ED(MAP2) were 0.3, 0.52 and >16.8 mg/kg/day, and therefore those for PI(MAP2) were 20, 4, and 0.5 for METH, PCA and MDMA, respectively. Although the results on mortality did not reflect changes in MAP2 gene expression, they suggest a remarkable difference for those amphetamines without substituents or with a halogen atom at the paraposition of the benzene ring, such as METH or PCA, when compared with MDMA-like substances.


Subject(s)
Actins/genetics , Central Nervous System Stimulants/toxicity , Cerebral Cortex/drug effects , Cytoskeletal Proteins/genetics , Gene Expression/drug effects , Methamphetamine/toxicity , Microtubule-Associated Proteins/genetics , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , p-Chloroamphetamine/toxicity , Animals , Blotting, Western , Brain Mapping , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Dose-Response Relationship, Drug , In Situ Hybridization , Injections, Intraperitoneal , Male , Rats , Rats, Wistar , Survival Analysis
2.
Neuropsychopharmacology ; 31(2): 431-41, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16123739

ABSTRACT

Patients with schizophrenia exhibit disturbances of orienting of attention. However, findings have been inconsistent. Pharmacologic challenges with hallucinogens have been used as models for psychosis. The NMDA antagonist state (PCP, ketamine) resembles undifferentiated psychoses with positive and negative symptoms, while the 5-HT(2A) agonist state (LSD, dimethyltryptamine (DMT)) is thought to be an appropriate model for psychoses with prominent positive symptoms. The aim of this study was to investigate orienting of attention in the human NMDA antagonist and 5-HT(2A) agonist models of psychosis. A total of 15 healthy volunteers participated in a randomized, double-blind, crossover study with a low and a high dose of DMT and S-ketamine, which elicited subtle 'prepsychotic' or full-blown psychotic symptoms (low and high dose, respectively). Nine subjects completed both experimental days with the two doses of both drugs. Overall, both hallucinogens slowed down reaction times dose dependently (DMT >S-ketamine) and DMT diminished the general response facilitating (alerting) effect of spatially neutral cues. Inhibition of Return (IOR), that is, the normal reaction time disadvantage for validly cued trials with exogenous cues and long cue target intervals, was blunted after both doses of DMT and the low dose of S-ketamine. IOR reflects an automatic, inhibitory mechanism of attention, which is thought to protect the organism from redundant, distracting sensory information. In conclusion, our data suggest a deficit of IOR in both hallucinogen models of psychosis, with the effect being clearer in the serotonin model. Blunted IOR may underlie or predispose to different psychotic manifestations, but particularly to those with prominent positive symptoms.


Subject(s)
Inhibition, Psychological , Ketamine/toxicity , N,N-Dimethyltryptamine/toxicity , Psychoses, Substance-Induced/etiology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Serotonin 5-HT2 Receptor Agonists , Adult , Attention/drug effects , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Middle Aged , Models, Biological , Neuropsychological Tests , Psychiatric Status Rating Scales , Psychometrics , Psychoses, Substance-Induced/physiopathology , Reaction Time/drug effects
3.
Addict Biol ; 10(3): 243-9, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16109585

ABSTRACT

Recent studies have revealed the effectiveness of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a highly selective antagonist of metabotropic glutamate receptors subtype 5 (mGluR5), in conditioned drug reward. In a previous study we showed that MPEP blocks expression of context-conditioned morphine- but not cocaine reward in the rat. The present study now examines the effectiveness of MPEP in the expression of context-conditioned food, MDMA ('ecstasy') or amphetamine reward. Therefore, three groups of rats were conditioned either to food, MDMA or amphetamine in the conditioned place preference (CPP) paradigm. After conditioning, CPP expression and locomotion were determined simultaneously in the presence and absence of the respective reward (i.e. food or drug), or after application of 50 mg/kg MPEP (the dose that was most effective in reducing morphine CPP expression in our previous study). As a result, MPEP reduced locomotion in all groups. Furthermore, only expression of amphetamine CPP was inhibited by MPEP, while expression of food and MDMA CPP was not affected, suggesting that the MPEP-induced inhibition of amphetamine CPP expression was not causally linked to the reduction of locomotion. Overall, we conclude that MPEP reduces expression of context-conditioned amphetamine but not MDMA or food reward.


Subject(s)
Amphetamine/metabolism , Choice Behavior/drug effects , Cocaine/antagonists & inhibitors , Conditioning, Psychological/drug effects , Feeding Behavior/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , Pyridines/pharmacology , Serotonin Agents/metabolism , Animals , Locomotion/drug effects , Male , Pyridines/administration & dosage , Rats , Rats, Sprague-Dawley , Reward
4.
Eur J Pharmacol ; 516(1): 34-9, 2005 May 23.
Article in English | MEDLINE | ID: mdl-15899478

ABSTRACT

It has recently been shown that 3,4-Methylenedioxymethamphetamine (MDMA) has an anti-parkinsonian effect in rodent models of Parkinson's disease. The mechanism of this anti-parkinsonian action is unknown. Opioids have been suggested to play a role in MDMA-induced behaviour. We therefore investigated MDMA and naloxone in the rat rotational behavioural model. Male Sprague-Dawley rats were lesioned unilaterally with 6-hydroxydopamine at the medial forebrain bundle. Administration of R/S-MDMA (5 mg/kg, s.c.) produced ipsilateral rotations. Naloxone (2, 5, 10 mg/kg, s.c.) did not produce rotations on its own but reduced the number of MDMA-induced ipsilateral rotations. This effect was not dose-dependent. In contrast to reports on mice, in unlesioned animals, naloxone (10 mg/kg, s.c.) did not block MDMA (5 mg/kg, s.c.)-induced hyperactivity in an open field in our experiment. It is concluded that endogenous opioids play a role in MDMA's action in the rat rotational behavioural model.


Subject(s)
Behavior, Animal/drug effects , Hallucinogens/pharmacology , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Naloxone/pharmacology , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Male , Motor Activity/drug effects , Narcotic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley , Time Factors
5.
Planta Med ; 71(2): 147-52, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15729623

ABSTRACT

An HPLC assay with fluorimetric detection of the arbutin metabolites hydroquinone glucuronide (2) and hydroquinone sulphate (6) in urine was developed and validated. Methylarbutin (4) and 6 were synthesised as reference substances. Compound 2 was prepared enzymatically from hydroquinone and uridine 5'-diphosphoglucuronic acid using the glucosyltransferase system of rat liver microsomes and enriched by two liquid-liquid and an additional solid phase extraction. Compound 2 as the main component of this purified product was identified by UV and fluorescence spectroscopy, by HPLC-MS, and by enzymatic hydrolysis to hydroquinone (5). The assay yields precise and accurate urine levels of 2, 5 and 6 in the concentration range expected after oral administration of recommended therapeutic doses of bearberry leaf extract. In a preliminary pharmacokinetic study on 3 volunteers the time-dependent renal excretion of arbutin metabolites 2, 5 and 6 was investigated after ingestion of an aqueous bearberry leaf extract containing an arbutin dose recommended by the German Kommission E. More than half of the administered dose of arbutin was excreted within 4 hours mainly in form of the metabolites 2 and 6 and more than 75 % of the total applied arbutin was excreted within 24 h. The elimination of 5 was negligible in 2 out of 3 volunteers. The excretion of this metabolite in the third test person reached 5.6 % of the total administered arbutin dose. The preliminary pharmacokinetic results confirm that renal elimination of toxicologically critical concentrations of the metabolite 5 will not be expected.


Subject(s)
Arbutin/urine , Arctostaphylos , Kidney/metabolism , Microsomes, Liver/metabolism , Phytotherapy , Plant Extracts/pharmacokinetics , Administration, Oral , Adult , Animals , Chromatography, High Pressure Liquid , Female , Humans , Male , Middle Aged , Plant Leaves , Rats , Rats, Sprague-Dawley
6.
Synapse ; 55(3): 148-55, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15602749

ABSTRACT

We have shown recently that 3,4-methylenedioxymethamphetamine (MDMA) has symptomatic antiparkinsonian activity in rodent models of Parkinson's disease. In search of its mechanism of action, we further investigated the enantiomers of MDMA in the rotational behavioral model and catalepsy test. Catalepsy testing was done in drug-naive unlesioned animals. The parkinsonian symptoms rigor and akinesia (i.e., catalepsy) were induced by intraperitoneal administration of haloperidol 0.5 mg/kg and measured repeatedly as descent latency from a horizontal bar and a vertical grid. MDMA and both its enantiomers were effective in counteracting haloperidol-induced catalepsy, but if given as racemic, the effects were more pronounced than with the enantiomers. For testing of rotational behavior, male Sprague Dawley rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA) at the medial forebrain bundle. Administration of S-MDMA (5 mg/kg) produced ipsilateral rotations. R-MDMA was far less effective in inducing ipsilateral rotations in 6-OHDA unilaterally lesioned rats, but when S-MDMA was given additionally rotations immediately increased. Regarding their overall antiparkinsonian effects, the S-enantiomer of MDMA was more effective than its R-congener. R-MDMA was able to increase the actions of S-MDMA.


Subject(s)
Adrenergic Uptake Inhibitors/pharmacology , Antiparkinson Agents/pharmacology , Catalepsy/drug therapy , Gait Disorders, Neurologic/drug therapy , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Parkinsonian Disorders/drug therapy , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/therapeutic use , Animals , Antiparkinson Agents/chemistry , Antiparkinson Agents/therapeutic use , Behavior, Animal/drug effects , Behavior, Animal/physiology , Catalepsy/chemically induced , Catalepsy/physiopathology , Denervation , Disease Models, Animal , Gait Disorders, Neurologic/chemically induced , Gait Disorders, Neurologic/physiopathology , Haloperidol , Male , N-Methyl-3,4-methylenedioxyamphetamine/chemistry , N-Methyl-3,4-methylenedioxyamphetamine/therapeutic use , Oxidopamine , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Rotation , Stereoisomerism
7.
J Sep Sci ; 27(7-8): 557-9, 2004 May.
Article in English | MEDLINE | ID: mdl-15335040

ABSTRACT

Methadone is widely used for the treatment of opioid dependence. HPLC and CE are widespread methods for drug monitoring and metabolism studies. Although the methods are widely used for methadone and its main metabolite EDDP [1, 2], a definite direct peak identification for EDDP enantiomers is not described. This study describes a method for specific identification of each peak in the chromatogram and electropherogram of methadone analysis. The result of the study demonstrates differences in the elution order of the enantiomers of methadone and EDDP due to the technique used for analysis. The elution order of EDDP using HPLC is interchanged with respect to the order of the peaks in the electropherogram.


Subject(s)
Methadone/analysis , Pyrrolidines/analysis , Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Indicators and Reagents , Methadone/chemistry , Methadone/isolation & purification , Pyrrolidines/chemistry , Pyrrolidines/isolation & purification , Stereoisomerism
8.
J Chromatogr Sci ; 42(6): 306-9, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15296530

ABSTRACT

In most cases the pharmacological activity of plant extracts is not assigned to single components and often not all active ingredients are known. Approaches other than those considering single compounds only to analyze plant material have proven helpful for a better characterization of extracts in their entirety. In this study extracts of willow bark are analyzed by high-performance thin-layer chromatography (HPTLC) and two different pharmacological tests [the 2,2'-azobis (2-amidinopropane) dihydrochloride reaction and the xanthine/xanthine oxidase reaction] with the help of multivariate data analysis. Described are two models using the results of the chromatographic study of 22 various extracts of willow bark and their pharmacological properties. The chromatographic data are obtained by a special TLC scanner that enables measurement of HPTLC tracks simultaneously in the range of lambda = 200-400 nm. Additionally, the developed models are used to predict the activity of another three extracts of willow bark demonstrating the quality of the model.


Subject(s)
Chromatography, Thin Layer/methods , Plant Bark/chemistry , Plant Extracts/analysis , Salix/chemistry , Multivariate Analysis , Plant Extracts/pharmacology
9.
Article in English | MEDLINE | ID: mdl-12906896

ABSTRACT

An enantioselective HPLC method has been developed and validated for the stereospecific analysis of N-ethyl-3,4-methylenedioxyamphetamine (MDE) and its major metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine (HME) and 3,4-methylenedioxyamphetamine (MDA). These compounds have been analyzed both from human plasma and urine after administration of 70 mg pure MDE-hydrochloride enantiomers to four subjects. The samples were prepared by hydrolysis of the o-glucuronate and sulfate conjugates using beta-glucuronidase/arylsulfatase and solid-phase extraction with a cation-exchange phase. A chiral stationary protein phase (chiral-CBH) was used for the stereoselective determination of MDE, HME and MDA in a single HPLC run using sodium dihydrogenphosphate, ethylendiaminetetraacetic acid disodium salt and isopropanol as the mobile phase (pH 6.44) and fluorimetric detection (lambda(ex) 286 nm, lambda(em) 322 nm). Moreover, a suitable internal standard (N-ethyl-3,4-methylenedioxybenzylamine) was synthesized and qualified for quantitation purposes. The method showed high recovery rates (>95%) and limits of quantitation for MDE and MDA of 5 ng/ml and for HME of 10 ng/ml. The RSDs for all working ranges of MDE, MDA and HME in plasma and urine, respectively, were less than 1.5%. After validation of the analytical methods in plasma and urine samples pharmacokinetic parameters were calculated. The plasma concentrations of (R)-MDE exceeded those of the S-enantiomer (ratio R:S of the area under the curve, 3.1) and the plasma half time of (R)-MDE was longer than that of (S)-MDE (7.9 vs. 4.0 h). In contrast, the stereochemical disposition of the MDE metabolites HME and MDA was reversed. Concentrations of the (S)-metabolites in plasma of volunteers were much higher than those of the (R)-enantiomers.


Subject(s)
3,4-Methylenedioxyamphetamine/analogs & derivatives , 3,4-Methylenedioxyamphetamine/pharmacokinetics , 3,4-Methylenedioxyamphetamine/blood , 3,4-Methylenedioxyamphetamine/urine , Adult , Chromatography, High Pressure Liquid , Cross-Over Studies , Double-Blind Method , Humans , Male , Middle Aged , Pilot Projects , Reproducibility of Results , Spectrometry, Fluorescence , Stereoisomerism
10.
Forensic Sci Int ; 134(2-3): 187-95, 2003 Jul 08.
Article in English | MEDLINE | ID: mdl-12850416

ABSTRACT

Calibration models for the quantitation of commonly used ecstasy substances have been developed using near infrared spectroscopy (NIR) in diffuse reflectance and in transmission mode by applying seized ecstasy tablets for model building and validation. The samples contained amphetamine, N-methyl-3,4-methylenedioxy-amphetamine (MDMA) and N-ethyl-3,4-methylenedioxy-amphetamine (MDE) in different concentrations. All tablets were analyzed using high performance liquid chromatography (HPLC) with diode array detection as reference method. We evaluated the performance of each NIR measurement method with regard to its ability to predict the content of each tablet with a low root mean square error of prediction (RMSEP). Best calibration models could be generated by using NIR measurement in transmittance mode with wavelength selection and 1/x-transformation of the raw data. The models build in reflectance mode showed higher RMSEPs using as data pretreatment, wavelength selection, 1/x-transformation and a second order Savitzky-Golay derivative with five point smoothing was applied to obtain the best models. To estimate the influence of inhomogeneities in the illegal tablets, a calibration of the destroyed, i.e. triturated samples was build and compared to the corresponding data of the whole tablets. The calibrations using these homogenized tablets showed lower RMSEPs. We can conclude that NIR analysis of ecstasy tablets in transmission mode is more suitable than measurement in diffuse reflectance to obtain quantification models for their active ingredients with regard to low errors of prediction. Inhomogeneities in the samples are equalized when measuring the tablets as powdered samples.


Subject(s)
Hallucinogens/analysis , N-Methyl-3,4-methylenedioxyamphetamine/analysis , Spectroscopy, Near-Infrared/methods , Tablets/chemistry , Amphetamines/analysis , Calibration , Central Nervous System Stimulants/analysis , Chromatography, High Pressure Liquid , Forensic Medicine/methods , Molecular Structure , Reproducibility of Results
11.
Arch Pharm (Weinheim) ; 336(3): 155-8, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12822180

ABSTRACT

A synthesis of two new active substances, DOMCl (1-(4-chloromethyl-2, 5-dimethoxyphenyl)-2-propanamine; 2) and DOMOM (1-(2, 5-dimethoxy-4-methoxymethylphenyl)-2-propanamine; 3), was developed. Unexpectedly, the Blanc reaction permitted successful synthesis of 2, 5-dimethoxyphenylpropylamine derivatives having a substituted methyl group in position 4 since solvation of the reactant occurs during the reaction. Afterwards, their affinities towards the 5-HT(2A) receptor were examined in 5-HT(2A) radioligand receptor binding assays. The study of these substances is of considerable interest because they were predicted, by preliminary molecular modeling studies based on mescalin units, to be potential new hallucinogens that should be added to the list of substances prohibited by law. It was assumed that DOMCl would be 82 times more potent as a hallucinogen than mescalin, and DOMOM would be 94 times more potent. The 5-HT(2A) radioligand receptor binding studies showed that the affinities of DOMCl and DOMOM for the 5-HT(2A) receptor are less than expected but are nevertheless 1.6 and 8.7 times higher, respectively, than that of mescalin. Therefore, scheduling these substances as potential drugs of abuse might be considered.


Subject(s)
Hallucinogens/chemical synthesis , Propane/chemical synthesis , Receptors, Serotonin/drug effects , Animals , Binding Sites , Binding, Competitive , Dose-Response Relationship, Drug , Drug Design , Hallucinogens/chemistry , Hallucinogens/pharmacology , In Vitro Techniques , Ligands , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Propane/analogs & derivatives , Propane/chemistry , Propane/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Structure-Activity Relationship
12.
Neurosci Lett ; 330(2): 193-7, 2002 Sep 20.
Article in English | MEDLINE | ID: mdl-12231444

ABSTRACT

The metabolism of MDA (3,4-methylenedioxyamphetamine), HMMA (3-hydroxy-4-methoxymethylamphetamine) and HME (3-hydroxy-4-methoxyethylamphetamin) of the popular designer drugs MDMA ('ecstasy', 3,4-methylenedioxymethamphetamine) and MDE ('eve', 3,4-methylenedioxyethylamphetamine) was determined in rat serum, whole blood and urine, as well as in whole brain structures (cortex and striatum) after subcutaneous administration of 20 mg/kg MDMA and MDE, respectively. MDMA and MDE were extracted from serum and homogenized brain structures using a solid-phase extraction procedure. The extracts were examined by a validated high-performance liquid chromatography procedure coupled with fluorimetric detection. Our results demonstrate that MDMA is metabolized to a higher degree than MDE, resulting in a higher concentration of neurotoxic dihydroxymetabolites and (S)-MDA. There was no difference between the metabolism of MDMA and MDE and its respective isomers. Different concentrations of the respective isomers of MDMA and MDE let us suggest an enantioselective metabolism for both MDMA and MDE.


Subject(s)
Brain/metabolism , Hallucinogens/blood , N-Methyl-3,4-methylenedioxyamphetamine/blood , Analysis of Variance , Animals , Brain Chemistry/drug effects , Cerebral Cortex/chemistry , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Chromatography, High Pressure Liquid/methods , Corpus Striatum/chemistry , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Designer Drugs , Gas Chromatography-Mass Spectrometry , Hallucinogens/metabolism , Hallucinogens/pharmacokinetics , Injections, Subcutaneous , Isomerism , N-Methyl-3,4-methylenedioxyamphetamine/metabolism , N-Methyl-3,4-methylenedioxyamphetamine/pharmacokinetics , Rats , Rats, Sprague-Dawley , Serotonin Agents/blood , Serotonin Agents/metabolism , Serotonin Agents/pharmacokinetics
13.
Neurosci Lett ; 330(3): 280-4, 2002 Sep 27.
Article in English | MEDLINE | ID: mdl-12270646

ABSTRACT

3,4-methylenedioxy-methylamphetamine (MDMA) ('Ecstasy') and its analogue 3,4-methylenedioxy-methylamphetamine (MDE) ('Eve') are well known illicit street drugs mainly abused by young people. In spite of the actual research going on, the classification of their abuse potential remains unclear. Since secondary reinforcers are the main factors responsible for craving and relapse, the aim of our study was to assess the potency of MDMA and MDE in a second order reinforcement paradigm, i.e. conditioned place preference (CPP). For the general assessment of our study conditions, we compared MDMA with amphetamine. Unexpectedly, no significant CPP for MDMA was found in contrast to amphetamine. Detailed analysis of current literature led us to the working hypothesis that social environment is crucial for the development of CPP. In a subsequent experiment we tested the influence of housing conditions on CPP using MDMA and demonstrated that isolated animals show significant CPP compared to group-housed ones. In order to better understand the rewarding mechanisms of Ecstasy-derivatives, we tested both the racemic drugs and the pure isomers in the CPP paradigm. Both MDMA's optical isomers and racemic MDMA showed significant CPP without notable differences, while MDE and its isomers completely failed to show any significant CPP. In conclusion, the mechanism by which MDMA induces addiction is much more complicated than assumed so far and more pronounced in isolated animals. The fact that both optical isomers of MDMA led to CPP implies that at least two pathways by which MDMA induces craving behaviour exist.


Subject(s)
3,4-Methylenedioxyamphetamine/pharmacology , Choice Behavior/drug effects , Conditioning, Operant/drug effects , Hallucinogens/pharmacology , N-Methyl-3,4-methylenedioxyamphetamine/pharmacology , Amphetamine/pharmacology , Animals , Central Nervous System Stimulants/pharmacology , Isomerism , Male , Rats , Rats, Sprague-Dawley , Reward , Social Isolation
14.
J Pharm Pharm Sci ; 5(3): 245-57, 2002.
Article in English | MEDLINE | ID: mdl-12553893

ABSTRACT

PURPOSE: Imaging the serotonin transporter (SERT) with Positron Emission Tomography (PET) provides a useful tool for understanding alterations of the serotonergic system. However, no optimal PET radiotracer for the SERT yet exists. The main purpose of this study was to design potential new and selective PET radiotracers for the SERT and to predict their binding affinity at both the SERT and the norepinephrine transporter. METHODS: Molecular Modeling was used for ligand design. Predictions of binding affinity were based on models generated by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). RESULTS: A series of 100 compounds were suggested. As diphenyl sulfide derivatives like [(11)C] DASB have recently proven to be promising PET ligands, rational modification of the diphenyl sulfide scaffold has been performed. The novel compounds were predicted to be selective high affinity SERT ligands. Important new ideas are the introduction of a fluoroethyl-oxycarbonyl group (ester) and a fluorethyl-carbonyl group (ketone), as well as a formyl group (aldehyde), and its corresponding oxime and imine. Another innovative suggestion is the replacement of the sulfur bridge with a cyanamide group and a fluoroethylamino group. CONCLUSIONS: The suggested compounds possess features providing new possibilities for carbon-11 or fluorine-18 labeling. Synthesis, biological testing, and screening for PET suitability are reasonable further steps.


Subject(s)
Carrier Proteins/chemistry , Membrane Glycoproteins/chemistry , Membrane Transport Proteins , Models, Molecular , Nerve Tissue Proteins , Radioisotopes/chemistry , Computational Biology , Drug Design , Ligands , Norepinephrine Plasma Membrane Transport Proteins , Protein Binding , Serotonin Plasma Membrane Transport Proteins , Structure-Activity Relationship , Sulfides/chemistry , Symporters/chemistry , Tomography, Emission-Computed
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