Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR.

4,4'-Dimethylaminorex (4,4'-DMAR) is a novel psychoactive substance (NPS) that appeared on the illicit drug market in addition to the psychostimulant 4-methylaminorex (4-MAR). Both substances are methylated derivatives of aminorex, an amphetamine-like anorectic used in the 1960ies and withdrawn from the marked due to severe cardiovascular toxicity. The aim of the present study was to characterize the in vitro pharmacological profiles of 4-MAR, 4,4'-DMAR, and 3,4-dimethylaminorex (3,4-DMAR, direx). We assessed norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney (HEK) 293 cells. We also assessed monoamine receptor and transporter binding affinities. 4,4'-DMAR potently inhibited all monoamine transporters (IC50<1 µM) with greater potency than 3,4-methlyenedioxymethamphetaime (MDMA) and displayed a higher serotonergic over dopaminergic preference, relatively similar to MDMA (DA transporter / 5-HT transporter inhibition ratio of 0.4 and 0.08 for 4,4'-DMAR and MDMA, respectively). In contrast, 4-MAR preferentially inhibited the NE and DA transporter, exhibiting a pharmacological profile more similar to amphetamine. Both 4-MAR and 4,4'-DMAR were also substrate releasers at the DAT. 3,4-DMAR only weakly inhibited the NE transporter and showed no relevant activity at the DA and 5-HT transporter. Binding affinities of all three aminorex derivatives at various monoamine receptors were negligible (Ki values >2 µM). The in vitro pharmacological profiles indicate that 4,4'-DMAR has comparable psychoactive properties and serotonergic toxicity to MDMA and may be more potent. 4-MAR is a psychostimulant similar to amphetamine or methamphetamine. 3,4-DMAR likely has only weak psychostimulant properties.

DARK Classics in Chemical Neuroscience: Aminorex Analogues.

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.

Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR).

The recent occurrence of deaths associated with the psychostimulant cis-4,4'-dimethylaminorex (4,4'-DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4-methylenedioxy-4-methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis- and trans-MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis-isomer (90%). Exposure of the cis-isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans-isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non-selective monoamine releasing agent (+)-3,4-methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis- and trans-4,4'-DMAR, were assessed under identical conditions. cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR were more potent than MDMA in their ability to function as efficacious substrate-type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR and trans-MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans-4,4'-DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring-substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side-effects after high dose exposure.

Using internet snapshot surveys to enhance our understanding of the availability of the novel psychoactive substance 4-methylaminorex and 4,4'-dimethylaminorex.

4,4'-Dimethylaminorex is a stimulant novel psychoactive substance (NPS) first detected in Europe in November 2012. It is a derivative of 4-methylaminorex, a substance controlled under Schedule 1 of the 1971 United Nations Convention on Psychotropic Substances. There is currently no information on the availability or cost of these substances from Internet suppliers. An Internet snapshot study was undertaken in English using established European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) methodology to determine the availability of 4-methylaminorex and 4,4'-dimethylaminorex in April 2014. Twenty Internet sites selling 4-methylaminorex were identified, 18 selling in US dollars and two in GB Pound Sterling. Fourteen (70 %) Internet sites had a minimum purchase amount of ≥10 g (compared to user doses of 10-25 mg). For the 18 suppliers selling in US$, 9 quoted a fixed price per gram irrespective of the amount ordered and 11 had a reducing price per gram with increasing purchase quantity (US$30.8 ± 34.2/g for 1 g purchase to US$15.2 ± 20.3/g for 1 kg purchase). Only one Internet site selling 4,4'-dimethylaminorex was identified, selling in Euros. The minimum purchase quantity was 500 mg. The price per gram reduced from 36.08/g for a 500 mg purchase to 2.20/g for a 100 g purchase. This Internet snapshot demonstrated that there was a greater availability from Internet suppliers of products advertised as 4-methylaminorex than 4,4'-dimethylaminorex, despite the 4-methylaminorex being an internationally controlled substance. Whilst this may reflect misunderstanding by suppliers, it has the potential to put those purchasing at risk of contravening border control and/or local law enforcement legislation. The use of methodology such as Internet snapshot surveys is of increasing interest to clinical/medical toxicologists in their understanding of the supply, availability and cost of novel psychoactive substances.

[Pulmonary hypertension and obesity]. / Hypertension artérielle pulmonaire et obésité

Obesity is a morbid condition with hemodynamic consequences affecting the systemic and pulmonary circulations leading to a risk of pulmonary hypertension. Data in the literature do not argue in favor of a direct relationship between pulmonary hypertension and obesity. These two conditions appear to be two distinct entities, the different co-morbidities observed in obesity favoring pulmonary hypertension. Certain co-morbidities, for instance use of anorexic agents, exhibit a clear relationship with pulmonary hypertension. There is also a possible relationship with left ventricular failure, hypoxemia, and other respiratory disorders (including obstructive sleep apnea), hypothyroidism, and thomboembolism.

Risk factors for pulmonary arterial hypertension.

The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. Moreover, definite epidemiologic data are rare and ideally should be obtained from epidemiologic surveys such as large case-control studies. The increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPH1 gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be hastened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection.

Anorexigen-related cardiopulmonary toxicity.

Three years after the withdrawal of fenfluramine and dexfenfluramine from the market, the magnitude and prevalence of their deleterious cardiopulmonary effects remain undetermined. The links between these anorexigens and valvular heart disease and primary pulmonary hypertension, however, are clearly established. Because some evidence indicates that the valvular lesions may regress with cessation of the drug, management guidelines are still in flux. Patient reassurance and close surveillance, including serial echocardiography in selected cases, are warranted.

Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension.

Anorexigens such as aminorex fumarate and dexfenfluramine are associated with the development of severe pulmonary hypertension (PH), which clinically and histopathologically is considered indistinguishable from idiopathic or primary pulmonary hypertension (PPH). For the current study, we asked whether anorexigen-associated PH is characterized by monoclonal pulmonary endothelial cell proliferation (such as in PPH) or, alternatively, is associated with a polyclonal endothelial cell proliferation as found in secondary PH. Analysis of clonality by the human androgen receptor assay was performed in microdissected endothelial cells of plexiform lesions of two patients with anorexigen-associated PH. The four plexiform lesions of Patient 1 and the six of Patient 2 with anorexigen-associated PH exhibited a monoclonal expansion of pulmonary endothelial cells, with a mean clonality ratio of 0.03 +/- 0.01 SE. Our results indicate that appetite suppressant-associated PH is identical to PPH not only in clinical and histopathologic features but also, at a molecular level, in terms of the monoclonal nature of the endothelial cell proliferation. The anorexigens may accelerate the growth of pulmonary endothelial cells in patients with predisposition to develop PPH.

Development of pulmonary aneurysm in primary pulmonary hypertension: a case report.

Selected cases of severe primary pulmonary arterial hypertension and associated pulmonary vascular disease have been related to the oral ingestion of aminorex fumarate, an anorexigen obviously responsible for an epidemic of primary pulmonary hypertension in Western Europe between 1967 and 1970. This report describes a fifteen year follow-up of a female patient with aminorex fumarate related pulmonary hypertension and the uncommon finding of the formation of an excessive fusiform pulmonary trunk aneurysm in the late stage of the disease process. The progressive clinical course was followed by serial chest x-ray films and repeat right heart catheterization. The diagnosis of a main stem pulmonary artery aneurysm was noninvasively established by two-dimensional echocardiography and confirmed by contrast-enhanced computed tomography and radionuclide blood pool imaging. The patient is alive, thus no histologic correlate of this entity is available at present.

Polymorphic debrisoquine and mephenytoin hydroxylation in patients with pulmonary hypertension of vascular origin after aminorex fumarate.

During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.

Aminorex and pulmonary hypertension. A review.

There was an epidemic of chronic pulmonary hypertension in Austria, the Federal Republic of Germany and Switzerland, starting in 1967, peaking in 1968/69, and disappearing after 1972. The mechanism leading to pulmonary hypertension was chronic precapillary vascular obstruction due to plexogenic pulmonary arteriopathy. There was a close geographic as well as temporal relation of the epidemic to the marketing and intake of the appetite depressing drug aminorex fumarate (Menocil). 10 years after the epidemic, half of the patients have died, usually of right heart failure. Of those surviving, half present a definite regression of the pulmonary vascular obstruction. Average survival after the initial diagnosis was 3.5 years in those patients who died. Their PA pressure (+22%) and pulmonary arteriolar resistance (+40%) was higher at the onset of the observation period if compared with the corresponding values of the survivors; also the incidence of right heart failure was significantly higher (84 vs. 58%). Among the surviving patients, the only difference between those with an improved and those with a worsened haemodynamic situation was the age at the beginning of the weight-reducing treatment, those with a progression being 10 years older. The probability of survival after 10 years is considerably higher in chronic pulmonary hypertension of vascular origin (CPHVO) after aminorex than in "classical" primary pulmonary hypertension (CPHVO of unknown cause) and in CPHVO due to recurrent silent pulmonary thromboembolism. This difference in prognosis is an argument in favour of the identity of chronic pulmonary hypertension developing after the intake of the appetite depressing drug aminorex.

Long-term follow-up of pulmonary hypertension in patients with and without anorectic drug intake.

Over a period of up to 18 years, 24 patients (mean age: 33.8 years) with primary vascular pulmonary hypertension (PVPH) of unknown aetiology (group A) and 18 subjects (mean age: 45.3 years) with PVPH due to anorectic drug intake (group B) were comparatively studied. The following main tendencies became apparent: 1) The 10-year cumulative survival rate in group A (0.31) was lower than in group B (0.63). 2) Patients of group A showed more marked X-ray and ECG signs of pulmonary hypertension and right ventricular hypertrophy in comparison with group B. In contrast to group B, the ECG signs of hypertrophy in group A increased during the observation period. 3) Mean pulmonary artery pressure (PAP) significantly increased in group A (from 48.8 to 61.0 mmHg), while it decreased (from 47.6 to 33.3 mmHg) in group B. 4) The diameter of the descending branch of the right pulmonary artery increased with rising PAP only in group A, while the relationship between PAP and the Sokolow-Lyon index was significant only for the whole group of PVPH patients but not for the subgroups A and B. A regression of pulmonary hypertension in patients with anorectic drug intake was obvious, in contrast to the course in patients with PVPH of unknown aetiology.

[Long-term course of primary vascular pulmonary hypertension with and without intake of appetite depressants]. / Langzeitverlauf der primär vaskulären pulmonalen Hypertonie mit und ohne Einnahme von Appetitzüglern.

1. The long-term follow-up of 22 patients with anorectic drug intake (aminorex fumarate) (AS) and PVPH is compared to 38 patients with PVPH of unknown etiology. 2. The 10-year cumulative survival rate is significantly higher for the AF-positive group (54 +/- 11%) than for the AF-negative patients (15 +/- 6%). 3. In terms of the hemodynamic parameters at the time of diagnosis, there were no differences between the two patient groups. 4. Hemodynamic serial controls in the AF-positive group often show a decrease in pulmonary pressure at rest, in contrast to the AF-negative group. However, in all but one of the patients with a pressure drop at rest there is a considerable increase in pulmonary pressure during exercise. 5. In neither group any correlation is to be found between pulmonary pressure and survival time.