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

research chemical Research chemicals are chemical substances used by scientists 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 o ...

and

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

stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

with

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

properties.

History

The stimulant properties of AFA were discovered serendipitously at

Sterling-Winthrop Sterling Drug was an American global pharmaceutical company, also known as Sterling Winthrop, Inc. in its last years (after the merger with Winthrop-Stearns Inc. which itself resulted from the merger of ''Winthrop Chemical Company Inc.'' and ' ...

in the midst of 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 antibiotics, 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 and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. 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. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...

than

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Am ...

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

and so it was singled out for further study. A small number of clinical trials were held in the 1970s, but when it was found that AFA exacerbated psychotic symptoms in schizophrenic patients and produced undesirable stimulant properties in geriatric depressives clinical evaluation of AFA was discontinued. 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 cla ...

dopamine pathways 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. Dopamine constitutes about 80% o ...

, and the

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dop ...

. Since 2013 AFA has been sold on the

gray market A grey market or dark market (sometimes confused with the similar term " parallel market") is the trade of a commodity through distribution channels that are not authorized by the original manufacturer or trade mark proprietor. Grey market pr ...

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 ...

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

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

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 the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

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 chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

system. Despite its different mechanism of action, amfonelic acid displays discriminatory substitution with 150% the stimulant potency of

dextroamphetamine Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance an ...

. 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 and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...

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 psychosi ...

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 (Spiroperidol; brand name: Spiropitan ( JP)) is a typical antipsychotic and research chemical belonging to the butyrophenone chemical class. It is licensed for clinical use in Japan as a treatment for schizophrenia. Additionally, spip ...

. 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 Broth microdilution is a method used to test the susceptibility of microorganisms to antibiotics. It is the most commonly used method to perform this test in the United States. __TOC__ Process During testing, multiple microtiter plates are filled ...

the MIC of AFA for

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...

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