Aminorex, sold under the brand names Menocil and Apiquel among others, is a

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

(

anorectic An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

)

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

. It was withdrawn from the market after it was found to cause

pulmonary hypertension Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...

(PPH). In the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

, aminorex is a Schedule I

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

. Aminorex, in the 2-amino-5-aryloxazoline group, was developed by

McNeil Laboratories McNeil Consumer Healthcare is an American medicals products company belonging to Kenvue consumer health group. It primarily sells fast-moving consumer goods such as Over-the-counter drug, over-the-counter drugs. History The company was founded ...

in 1962. It is closely related to 4-methylaminorex (4-MAR). Aminorex has been shown to have locomotor-stimulant effects, lying midway between

dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

. Aminorex effects have been attributed to the release of

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

s. It can be produced as a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of the

deworming Deworming (sometimes known as worming, drenching or dehelmintization) is the giving of an anthelmintic drug (a wormer, dewormer, or drench) to a human or animals to rid them of helminths parasites, such as roundworm, flukes and tapeworm. Pu ...

medication

levamisole Levamisole, sold under the brand name Ergamisol among others, is a medication used to treat parasitic worm infections, specifically ascariasis and hookworm infections. It is taken by mouth. Side effects may include abdominal pain, vomiting, ...

, which is sometimes used as a cutting agent of illicitly produced

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

Pharmacology

Pharmacodynamics

Aminorex is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). Its values for induction of monoamine release are 26.4nM for

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

, 49.4nM for

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

, and 193nM for

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

. In addition to its monoamine-releasing activity, aminorex is a weak

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Its values for activation of these receptors are 4,365nM for 5-HT_2A, 870nM for 5-HT_2B, and 525nM for 5-HT_2C. Activation of serotonin 5-HT_2B receptors by aminorex, either directly via agonism or indirectly via serotonin release, has been implicated in the development of

pulmonary arterial hypertension Pulmonary arterial hypertension (PAH) is a syndrome in which the blood pressure in the pulmonary arteries and pulmonary arterioles (the blood vessels located proximal to the capillary bed, the site of oxygen exchange in the lungs) is elevated. T ...

and cardiac valvulopathy with the drug. However, its for serotonin 5-HT_2B receptor activation is 33-fold higher than its value for induction of norepinephrine release and is almost 50-fold less potent than the serotonin 5-HT_2B receptor agonism of dexnorfenfluramine. This seems to call into question the role of direct agonism of the serotonin 5-HT_2B receptor in the

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

of aminorex. Along similar lines, chlorphentermine, a related drug that has also been associated with such adverse effects, shows negligible direct serotonin 5-HT_2B receptor agonistic activity. However, it is possible that

s of aminorex and chlorphentermine might be more potent in this action. Aminorex does not appear to have been assessed at the

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1). However, several

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

s of aminorex, such as 4-methylaminorex (4-MAR) and 4,4'-dimethylaminorex (4,4'-DMAR), have been found to be inactive at the mouse and rat TAAR1. Many other monoamine releasing agents (MRAs), such as many

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

s, are rodent and/or human TAAR1 agonists. Activation of the TAAR1 may auto-inhibit and thereby constrain the monoaminergic effects of these agents. Lack of TAAR1 agonism in the case of aminorex analogues might enhance their effects relative to MRAs possessing TAAR1 agonism.

Chemistry

Aminorex is a member of the 2-amino-5-phenyloxazoline group. It is structurally related to the

substituted amphetamine Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...

s like

and to the

substituted phenylmorpholine Substituted phenylmorpholines, or substituted phenmetrazines alternatively, are chemical derivatives of 2-phenylmorpholine or of the psychostimulant drug phenmetrazine. Most such compounds act as Monoamine releasing agent, releasers of monoamine ...

s like

phenmetrazine Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first chemical synthesis, synthesized in 1952 and originally used as an appetite suppressant, but withdrawn drug, withdrawn from the market in the 1980s due to ...

. A variety of

s and analogues of aminorex are known. These include 2'-fluoro-4-methylaminorex (2F-MAR), 2C-B-aminorex, 3',4'-methylenedioxy-4-methylaminorex (MDMAR), 4'-bromo-4-methylaminorex (4B-MAR), 4'-chloro-4-methylaminorex (4C-MAR), 4'-fluoro-4-methylaminorex (4F-MAR), 4-methylaminorex (4-MAR), 4,4'-dimethylaminorex (4,4'-DMAR), clominorex, cyclazodone, fenozolone, fluminorex,

pemoline Pemoline, formerly sold under the brand name Cylert among others, is a stimulant medication which was used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy,- it has since been discontinued in most countries due ...

, and thozalinone, among others.

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 In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

synthesis involves addition/cyclization reaction of 2-amino-1-phenylethanol with

cyanogen bromide Cyanogen bromide is the inorganic compound with the chemical formula, formula BrCN. It is a colorless solid that is widely used to modify biopolymers, fragment proteins and peptides (cuts the C-terminus of methionine), and synthesize other compo ...

. 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.

History

It was discovered in 1962 by Edward John Hurlburt, and was quickly found in 1963 to have an

effect in

rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' (pack rats), '' Bandicota'' (bandicoo ...

s. It was introduced as a prescription appetite suppressant in

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

Switzerland Switzerland, officially the Swiss Confederation, is a landlocked country located in west-central Europe. It is bordered by Italy to the south, France to the west, Germany to the north, and Austria and Liechtenstein to the east. Switzerland ...

and

Austria Austria, formally the Republic of Austria, is a landlocked country in Central Europe, lying in the Eastern Alps. It is a federation of nine Federal states of Austria, states, of which the capital Vienna is the List of largest cities in Aust ...

in 1965, but was withdrawn in 1972 after it was found to cause

in approximately 0.2% of patients, and was linked to a number of deaths.

References

{{Chemical classes of psychoactive drugs 5-HT2B agonists 5-HT2C agonists Aminorexes Anorectics Cardiotoxins Norepinephrine-dopamine releasing agents Respiratory toxins Stimulants Withdrawn drugs