Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, meaning it has high abuse potential, no accepted medical use, and a poor safety profile. Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil Laboratories in 1962. It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine. Aminorex effects have been attributed to the release of catecholamines. It can be produced as a metabolite of the worming medication levamisole, which is sometimes used as a cutting agent of illicitly produced cocaine.

Pharmacology

Pharmacodynamics

Aminorex is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). Its EC50 values for induction of monoamine release are 26.4nM for norepinephrine, 49.4nM for dopamine, and 193nM for serotonin. In addition to its monoamine-releasing activity, aminorex is a weak agonist of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. Its EC50 values for activation of these receptors are 4,365nM for 5-HT2A, 870nM for 5-HT2B, and 525nM for 5-HT2C. Activation of serotonin 5-HT2B receptors by aminorex, either directly via agonism or indirectly via serotonin release, has been implicated in the development of pulmonary arterial hypertension and cardiac valvulopathy with the drug. However, its EC50 for serotonin 5-HT2B receptor activation is 33-fold higher than its EC50 value for induction of norepinephrine release and is almost 50-fold less potent than the serotonin 5-HT2B receptor agonism of dexnorfenfluramine. This seems to call into question the role of direct agonism of the serotonin 5-HT2B receptor in the toxicity of aminorex. Along similar lines, chlorphentermine, a related drug that has also been associated with such adverse effects, shows negligible direct serotonin 5-HT2B receptor agonistic activity. However, it is possible that metabolites of aminorex and chlorphentermine might be more potent in this action.

History

It was discovered in 1962 by Edward John Hurlburt, and was quickly found in 1963 to have an anorectic effect in rats. It was introduced as a prescription appetite suppressant in Germany, Switzerland and Austria in 1965, but was withdrawn in 1972 after it was found to cause pulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths.

Synthesis

The synthesis was first reported in a structure-activity relationship study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent than D-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects. The racemic synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol with cyanogen bromide. A similar synthesis has been also published. In a search for a cheaper synthetic route, a German team developed an alternative route which, by using chiral styrene oxide, allows an enantiopure product.