Amfonelic acid (AFA; WIN 25,978) is a

research chemical Research chemicals are chemical substances which scientists use for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human ...

and

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

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, ...

with

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

properties. Limited clinical trials have been conducted, and it is primarily used in scientific research.

History

The stimulant properties of AFA were discovered incidentally at

Sterling-Winthrop Sterling Drug was an American based global pharmaceutical company. It was also known as Sterling Winthrop, Inc., after the merger with Winthrop-Stearns Inc. which itself resulted from the merger of Winthrop Chemical Company Inc. and Frederick Ste ...

during research on the antibiotic

nalidixic acid Nalidixic acid (tradenames Nevigramon, NegGram, Wintomylon and WIN 18,320) is the first of the synthetic quinolone antibiotics. In a technical sense, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that ...

. In addition to behaving as an antibiotic, it was found that many derivatives of nalidixic acid have either stimulant or depressant effects on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. Researchers at Sterling-Winthrop found that AFA had a higher potency and

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

than

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 ...

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 ...

, leading to further study of the drug. A small number of clinical trials were held in the 1970s, but clinical evaluation of AFA was discontinued after it was found that AFA exacerbated psychotic symptoms in schizophrenic patients and produced undesirable stimulant properties in geriatric depressives. AFA remains a widely used pharmacological tool for study of the brain's

reward system The reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and c ...

dopamine pathways Dopaminergic pathways (dopamine pathways, dopaminergic projections) in the human brain are involved in both physiological and behavioral processes including movement, cognition, executive functions, reward, motivation, and neuroendocrine contro ...

, and the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

. Since 2013, AFA has been sold on the

grey market A grey market or dark market (sometimes confused with the similar term "parallel import, parallel market") is the trade of a commodity through distribution channels that are not authorised by the original manufacturer or trademark proprietor. ...

and there are numerous anecdotal reports detailing its non-medical use.

Pharmacology

In studies, it proved to be a potent and highly selective

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

(DRI) in rat brain preparations. A study found a moderately long

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of approximately 12 hours and a dopaminergic potency approximately 50 fold that of

methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

in rat brain preparations. Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in 5HT and 5HIAA. Amfonelic acid displays no activity in the

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 ...

system. Despite its different mechanism of action, amfonelic acid displays

discriminatory substitution Discrimination is the process of making unfair or prejudicial distinctions between people based on the groups, classes, or other categories to which they belong or are perceived to belong, such as race, gender, age, class, religion, or sexu ...

with 150% the stimulant potency of

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 ...

. Amfonelic acid has been shown to be neuroprotective against

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 ...

damage to dopamine neurons. It also increases the effects of the antipsychotic drugs

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

trifluoperazine Trifluoperazine, marketed under the brand name Stelazine among others, is a typical antipsychotic primarily used to treat schizophrenia. It may also be used short term in those with generalized anxiety disorder but is less preferred to benzodiaze ...

and

spiperone Spiperone, also known as spiroperidol and sold under the brand name Spiropitan (( JP)) is a typical antipsychotic of the butyrophenone family related to haloperidol. It is approved for clinical use in Japan as a treatment for schizophrenia. Pha ...

. Rats are shown to self-administer amfonelic acid in a dose-dependent manner. Though AFA was discovered in the course of antibiotic research, there is very little data available on the drug's antimicrobial activity. In 1988, the biologist G.C. Crumplin wrote, " FAis less active against bacteria than are many other 4-quinolones, but studies in our laboratory on selected mammalian cell lines have shown it to be markedly more toxic to these cells than are the 4-quinolones that are more active antibacterial agents. Furthermore, it can be shown that sublethal doses induced marked changes in the pattern of proteins produced by the cell, thus suggesting a possible effect of 4-quinolones on gene transcription in mammalian cells." When evaluated via broth microdilution the MIC of AFA for

Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

is 125 μg/mL, a concentration thirty times higher than the MIC for nalidixic acid in the same E. coli strain.

References

External links

Harper's Magazine: Sad Pink Monkey Blues

KEGG PATHWAY DATABASE : AMFONELIC ACID
{{Monoamine reuptake inhibitors Dopamine reuptake inhibitors WIN compounds Naphthyridines Enoic acids Euphoriants Stimulants

History

Pharmacology

See also

References

External links