The stimulant properties of AFA were discovered incidentally atSterling-Winthrop during research on the antibioticnalidixic acid.[1] In addition to behaving as an antibiotic, it was found that many derivatives of nalidixic acid have either stimulant or depressant effects on thecentral nervous system.[2] Researchers at Sterling-Winthrop found that AFA had a higher potency andtherapeutic index thancocaine oramphetamine, leading to further study of the drug.[1][3] 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.[1] AFA remains a widely used pharmacological tool for study of the brain'sreward system,dopamine pathways, and thedopamine transporter.[1] Since 2013, AFA has been sold on thegrey market and there are numerous anecdotal reports detailing itsnon-medical use.[1]
In studies, it proved to be a potent and highly selectivedopamine reuptake inhibitor (DRI) in rat brain preparations.[4][5] A study found a moderately longhalf-life of approximately 12 hours and a dopaminergic potency approximately 50 fold that ofmethylphenidate in rat brain preparations.[6] Despite lack of direct serotonin activity, rats treated with subchronic doses of amfonelic acid display subsequent decreases in5HT and5HIAA.[7] Amfonelic acid displays no activity in thenorepinephrine system.[8]
Despite its different mechanism of action, amfonelic acid displaysdiscriminatory substitution with 150% the stimulant potency ofdextroamphetamine.[9] Amfonelic acid has been shown to be neuroprotective againstmethamphetamine damage to dopamine neurons.[10] It also increases the effects of the antipsychotic drugshaloperidol,trifluoperazine andspiperone.[11] Rats are shown to self-administer amfonelic acid in a dose-dependent manner.[12]
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, "[AFA] is 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."[13] When evaluated viabroth microdilution theMIC of AFA forEscherichia coli is 125 μg/mL, a concentration thirty times higher than the MIC for nalidixic acid in the same E. coli strain.[1]
^US patent 3590036, "Naphthyridine-3-carboxylic Acids, Their Derivatives and Preparation Thereof"
^Aceto MD, Botton I, Martin R, Levitt M, Bentley HC, Speight PT (1970). "Pharmacologic properties and mechanism of action of amfonelic acid".European Journal of Pharmacology.10 (3):344–54.doi:10.1016/0014-2999(70)90206-2.PMID4393073.
^Fuller RW, Perry KW, Bymaster FP, Wong DT (March 1978). "Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release in vitro and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats".The Journal of Pharmacy and Pharmacology.30 (3):197–8.doi:10.1111/j.2042-7158.1978.tb13201.x.PMID24701.S2CID28881012.
^McMillen BA, Shore PA (July 1978). "Amfonelic acid, a non-amphetamine stimulant, has marked effects on brain dopamine metabolism but not noradrenaline metabolism: association with differences in neuronal storage systems".The Journal of Pharmacy and Pharmacology.30 (7):464–6.doi:10.1111/j.2042-7158.1978.tb13293.x.PMID27622.S2CID34793566.
^Izenwasser S, Werling LL, Cox BM (June 1990). "Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex".Brain Research.520 (1–2):303–9.doi:10.1016/0006-8993(90)91719-W.PMID2145054.S2CID24436917.
^McMillen BA, Scott SM, Williams HL (1991). "Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function".Journal of Neural Transmission. General Section.83 (1–2):55–66.doi:10.1007/BF01244452.PMID2018630.S2CID13008483.
^Agmo A, Belzung C, Rodríguez C (1997). "A rat model of distractibility: effects of drugs modifying dopaminergic, noradrenergic and GABAergic neurotransmission".Journal of Neural Transmission.104 (1):11–29.doi:10.1007/BF01271291.PMID9085190.S2CID19112365.
^Aceto MD, Rosecrans JA, Young R, Glennon RA (April 1984). "Similarity between (+)-amphetamine and amfonelic acid".Pharmacology, Biochemistry, and Behavior.20 (4):635–7.doi:10.1016/0091-3057(84)90316-2.PMID6728880.S2CID30259648.
^Pu C, Fisher JE, Cappon GD, Vorhees CV (June 1994). "The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopaminergic terminal degeneration and astrocytic response in rat striatum".Brain Research.649 (1–2):217–24.doi:10.1016/0006-8993(94)91067-7.PMID7953636.S2CID23292364.
^Waldmeier PC, Huber H, Heinrich M, Stoecklin K (January 1985). "Discrimination of neuroleptics by means of their interaction with amfonelic acid: an attempt to characterize the test".Biochemical Pharmacology.34 (1):39–44.doi:10.1016/0006-2952(85)90097-8.PMID2857083.
^Crumplin GC (1988). "Aspects of chemistry in the development of the 4-quinolone antibacterial agents".Reviews of Infectious Diseases. 10 Suppl 1 (10): S2-9.doi:10.1093/clinids/10.Supplement_1.S2.PMID3279494.
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