4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 lM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings.4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative originally synthesized and evaluated as an anorectic drug more than 40 years ago [1]. Subsequently, it was demonstrated that MTA is a potent, selective and non-neurotoxic serotonin (5-HT)-releasing agent in vitro [2,3] and in vivo [4], an effect that is mediated via the 5-HT transporter (SERT) [5,6]. MTA gained notoriety in the late 1990s as a street drug commonly known as 'flatliner', and its use has been associated with severe intoxications and several deaths [7][8][9][10]. Even though MTA is usually regarded as a selective serotonergic agent, it also potently inhibits monoamine oxidase-A (MAO-A) [4,11], and both hyperthermia [12] and aortic contraction [13] induced by MTA in rodent models can be blocked by a-adrenergic antagonists. In addition, it has been shown that MTA induces dopamine (DA) release from rat striatal synaptosomes pre-loaded with [ 3
Haemodilution in nine neonates resulted in significant mean (SEM) decrease of packed celi volume (0.67 (0.01) to 0-55 (0.01)) and increases in cardiac output (250 (16) to 308 (25) ml/min/kg) and blood flow velocities of the internal carotid artery and the coeliac artery (+20%). However, red cell flows in the aorta, carotid and coeliac arteries did not change during haemodilution, thereby indicating that haemodilution did not improve oxygen transport. (Arch Dis Child 1994; 71: F53-F54) Neonatal polycythaemia increases the risk of pulmonary hypertension, renal failure, necrotising enterocolitis, cerebral ischaemia, intracranial haemorrhage, and developmental retardation.' The clinical manifestations of polycythaemia result from the rise in blood viscosity.2 Previous studies have shown that cardiac output and cerebral blood flow velocity in polycythaemic neonates increased more than 30% during isovolaemic haemodilution (partial exchange transfusion). 3 Blood flow in gastrointestinal arteries of polycythaemic infants has not been studied. However, experiments in puppies have shown that polycythaemia decreases gastrointestinal blood flow by more than 40%.4 The present study was designed to evaluate the effects of polycythaemia and haemodilution on cardiac output and blood flow velocities of cerebral and coeliac arteries in newborn infants.were clamped within 20 seconds of birth.In the polycythaemic infants, isovolaemic haemodilution was performed with serum (Biseko, Biotest) via an umbilical vein catheter. The haemodilution procedure lasted about two hours and was continued until the packed cell volume was about 055.Cardiovascular measurements in the polycythaemic infants were done before and one to two hours after haemodilution. During the examinations, infants were either sleeping or quiet and in supine position. Blood flow velocities and cardiac output were measured using an Interspec XL pulsed Doppler ultrasound system (Interspec Inc). Details of the cardiac output method have been reported elsewhere.5 Systolic blood flow velocities were measured using a 5-0 MHz pulsed Doppler transducer. The arteries were identified by duplex scan mode. The right and left internal carotid artery were localised via the anterior fontanelle. As there were no significant differences between the two internal carotid arteries, the mean velocities of both arteries were calculated for each infant. The coeliac artery was localised by ultrasound from a longitudinal abdominal section and blood flow velocity was determined close to the origin of the artery from the abdominal aorta.Packed cell volume was determined by the microhaematocrit method. Mean arterial blood pressure was measured in the right and left upper arm using an oscillometric technique (Dinamap 847, Critikon). Systemic flow resistance was calculated as mean pressure to cardiac output ratio.
Although substrate conversion mediated by human monoaminooxidase (hMAO) has been associated with the deprotonated state of their amine moiety, data regarding the influence of protonation on substrate binding at the active site are scarce. Thus, in order to assess protonation influence, steered molecular dynamics (SMD) runs were carried out. These simulations revealed that the protonated form of the substrate serotonin (5-HT) exhibited stronger interactions at the protein surface compared to the neutral form. The latter displayed stronger interactions in the active site cavity. These observations support the possible role of the deprotonated form in substrate conversion. Multigrid docking studies carried out to rationalize the role of 5-HT protonation in other sites besides the active site indicated two energetically favored docking sites for the protonated form of 5-HT on the enzyme surface. These sites seem to be interconnected with the substrate/inhibitor cavity, as revealed by the tunnels observed by means of CAVER program. pK(a) calculations in the surface loci pointed to Glu³²⁷, Asp³²⁸, His⁴⁸⁸, and Asp¹³² as candidates for a possible in situ deprotonation step. Docking analysis of a group of inhibitors (structurally related to substrates) showed further interactions with the same two docking access sites. Interestingly, the protonated/deprotonated amine moiety of almost all compounds attained different docking poses in the active site, none of them oriented to the flavin moiety, thus producing a more variable and less productive orientations to act as substrates. Our results highlight the role of deprotonation in facilitating substrate conversion and also might reflect the necessity of inhibitor molecules to adopt specific orientations to achieve enzyme inhibition.
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