Fenozolone, ≥98%

Chemical Information:

Technical Information:

Background:

Fenozolone (N-Ethylpemoline) is an approximately 2x - 4x more potent N-ethyl derivative of Pemoline. According to patents filed by the inventors, Fenozolone exhibits central nervous system stimulating properties and anorexigenic properties that are more potent than those of Pemoline, and more potent than those of N-methyl-substituted Pemoline. At the same time, Fenozolone also presents a more favorable therapeutic index and margin of safety than Pemoline or N-methyl-substituted Pemoline.[1]

PubChem categorizes Fenozolone in the “sympathomimetics” class of chemical compounds. This group of compounds mimic the effects of stimulating postganglionic adrenergic sympathetic nerves, either by directly stimulating adrenergic receptors or by indirectly provoking the release of adrenergic transmitters.[2]

According to the original patents, N-methyl-Pemoline and N-propyl-Pemoline, Fenozolone showed the following advantages in comparison to Pemoline:

1. Fenozolone acted more rapidly and had a longer lasting effect on the spontaneous activity of the mouse, and its effect was not reduced if it was administered orally; F
2. Fenozolone was more active in the rotating rod test, more effective in antagonizing the central nervous depressant activity of chloral hydrate, was a more effective anorexigenic, and produced a more prolonged effect in the forced swimming test than the other compounds;
3. Fenozolone had a greater therapeutic index (safety margin between effective and lethal doses) than the other compounds. [1] 

Fenozolone’s parent compound, Pemoline, was used as a nervous system stimulant for the treatment of attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD).[3] However, since its first use in 1975, it was associated with 21 cases of liver failure, at least 13 of which resulted in death. It was subsequently pulled from the market for concerns over hepatotoxicity.[4] However, Pemoline is chemically more closely related to Thiozoline than to Pemoline.[5]

Modes of action: 

Fenozolone’s modes of action are not yet fully understood. However, it can be theorized that, due to its similarity to Thozalinone, its mechanism of action should be somewhat similar, and perhaps somewhat similar to that of Pemoline.

Pemoline is considered to be dopaminergic, but its precise method of action hasn't been definitively determined. Pemoline has minimal affinity for norepinephrine receptors, and thus has minimal sympathomimetic side effects compared with typical dopaminergic central nervous system stimulants such as methylphenidate and dexamphetamine.[6] 

Interestingly, Pemoline also fails to demonstrate a potential for self-administration in primates, and is considered to have a reduced risk of dependence relative to more typical dopaminergic stimulants. Furthermore, anecdotal evidence has hinted that Pemoline and some related compounds in the 2-amino-5-aryl oxazoline and 2-amino-5-aryl-4-oxazolidinone classes might exhibit nootropic or cognitive enhancement characteristics, potentially additional to, or unique from, those associated with typical dopaminergic central nervous system stimulants such as methylphenidate and dexamphetamine.

With regards to Thozalinone, the compound has undergone human clinical trials investigating its potential use in the treatment of depression[7] and obesity[8], and was described as "most interesting", because of its "potency, safety, and duration of action"[9]. A study on its pharmacological profile found:

“Thozalinone has been shown to possess some pharmacologic actions similar to those of amphetamine and imipramine, but with important differences. It is less toxic than amphetamine, and its margin of safety in mice is greater. The stimulant action does not progress to tremors or convulsions as the dosage is increased.

The anorexigenic activity of thozalinone is more pronounced and longer lasting than that of amphetamine. There is no evidence of the development of tolerance. The cardiovascular side effects of thozalinone are minimal, and analeptic actions are absent.” [5]

(For more information on the mechanism of action of Thozalinone, please see our product description for this compound).

In 1978, a French study examined the effects of Levophacetoperane, Pemoline, Fenozolone, and Centrophenoxine on catecholamines and serotonin uptake in various parts of the rat brain.  In vitro, all drugs (except Centrophenoxine) inhibited norepinephrine uptake in a competitive manner, in rat hypothalamus and cortex, and dopamine uptake in corpus striatum and cortex. These effects were seen at higher concentrations than d.l. amphetamine – and only d.I. amphetamine was found to inhibit serotonin uptake in the hypothalamus.[10]

Further Scientific research:

Please note that this is not a complete account of the available literature on this compound. The studies below are meant to give the reader a summary of different types of experiments conducted using this compound. For more information, please consult the PubMed database.

Clinical Reviews:

In 2012, Fenozolone was included as an ADD/ADHD medication in a BMJ study to investigate the prevalence, determinants and spectrum of attention-deficit hyperactivity disorder (ADHD) medication and its associations with socioeconomic status (SES), health-related behaviour and living conditions.[11]

Apart from that, there are no literature reviews or meta-analyses available as yet for this compound, due to a relative lack of research.

Human studies: 

In 1972, French researchers published results of a clinical trial of Fenozolone. Unfortunately, no further information is currently available about this trial. [12]

In 1999, the effects on cerebral motor activity of a single dose of Fluoxetine (20 mg) (an inhibitor of serotonin reuptake) and Fenozolone (20 mg/50 kg), were assessed by functional magnetic resonance imaging. Participants performed sensorimotor tasks with the right hand, in two separate sessions – the first without the use of drugs, and the second measuring their effects. The results showed a large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices, for both compounds – i.e., modulation of cerebral motor activity.[13]

In 1982, researchers discovered a method of detecting Fenozolone, Pemoline, and Thozalione in human urine, through convertion by acid hydrolysis to their common hydrolysis product, 5-phenyl-2,4-oxazolidinedione. Unlike the parent compounds, this product can be detected with high sensitivity and selectivity by thin layer chromatography.[14]

Animal studies:

The original patents stated that Fenozolone exhibited stimulant and antidepressant effects in mice, for at least 4 to 5 hours. Fenozolone was effective in a number of measures, including reversing the sedative effects of chlorpromazine, reducing sleep induced by barbiturates, and counteracting the respiratory depression induced by morphine. [1]

In addition, the antidepressant and anti-fatigue effects of the compound were demonstrated in the forced swimming test, in which it showed a more consistent and more powerful effect than the parent compound, Pemoline. Furthermore, according to the inventor's patents, Fenozolone showed very distinct anorexigenic properties, reducing freely fed dog's food intake by 50% or more when administered in amounts that did not cause signs of excitation or overstimulated behavior.[15]

Toxicity Cases:

No toxicity cases have been reported for this compound. Its parent molecule, Pemoline, was associated with severe hepatotoxicity in several cases, of which several resulted in death. However, Fenozoline is chemically more similar to the related Thozalinone than to Pemoline, and no toxicity cases have been reported for that compound.

The VirtualToxLab™ 5.8 is an in silico tool used for predicting the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The potential binding affinity of selected compounds to protein classes: nuclear receptor class I (AR, ERα, ERβ, GR, MR, PR), nuclear receptor class II (LXR, PPARγ, TRα TRβ), cytochromes (1A2, 2C9, 2D6, 3A4), hERG, and AhR, is tested by the tool to determine a toxicity rating.  The tool is based solely on thermodynamic considerations and does not include any ADME (adsorption, distribution, metabolism, elimination) aspects. 

According to this tool, Fenozolone has a predicted toxicity rating of 0.306 / 0.326 (for R / S enantiomers, respectively). This rating falls into the lowest toxicity class (any rating under 0.4 falls into this class) and Fenozolone is “unlikely to show any adverse effect (triggered by the 16 target proteins tested in the VirtualToxLab), but may bind weakly to a single target class.” [16]

References:

• [1] Les Laboratoires Dausse. (1962). 5-Phenyl-2-(aryl) alkylamino-4-oxazolinones. Les Laboratoires Dausse, assignee. Patent BE613985.
• [2] Fenozolone. Compound Summary for CID 71682. (2018). PubChem, Open Chemistry Database. [online] Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Fenozolone [Accessed 3 October 2018]
• [3] Drug Label: Cylert (Pemoline). (2002). [Pdf]. FDA. [online] Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/016832s022_017703s018lbl.pdf
• [4] Pemoline – withdrawn due to liver toxicity risk. (2005). In: WHO Pharmaceuticals Newsletter, No. 5. World Health Organization (WHO).
• [5] Greenblatt, E. N., & Osterberg, A. C. (1965). Some pharmacologic properties of thozalinone, a new excitant. Toxicology and Applied Pharmacology, 7(4), 566–578.
• [6] Sciencedirect.com. (2018). Pemoline - an overview. ScienceDirect Topics. [online] Available at: https://www.sciencedirect.com/topics/neuroscience/pemoline  [Accessed 3 Oct. 2018].
• [7] Gallant, D.M., Bishop, M.P., Scrignar, C.B., Hornsby, L., Moore, B., Inturrisi, B.B. (1966). A double-blind study of thozalinone (C1 39,808) in depressed outpatients. Curr Ther Res Clin Exp, 8(12):621-2.
• [8] Leite, A.C., Liepen, L,L,, Costa, V.P. (1971). [Clinical trial of Stimsem Thozalinone in the treatment of obese patients]. Rev Bras Med, 28(9):475-8.
• [9] Greenblatt, E.N., Osterberg, A.C. (1965). Some pharmacologic properties of thozalinone, a new excitant. Toxicol Appl Pharmacol, 7(4):566-78.
• [10] Ramirez, A., Vial, H., Barailler, J., Pacheco, H. (1978). [Effects of levophacetoperane, pemoline, fenozolone, and centrophenoxine on catecholamines and serotonin uptake in various parts of the rat brain]. (Article in French). C R Acad Sci Hebd Seances Acad Sci D, 187(1):53-6.
• [11] Knopf, H., Hölling, H., Huss, M., & Schlack, R. (2012). Prevalence, determinants and spectrum of attention-deficit hyperactivity disorder (ADHD) medication of children and adolescents in Germany: results of the German Health Interview and Examination Survey (KiGGS). BMJ Open, 2(6), e000477.
• [12] Mundler, F. (1972). [Clinical trial of a new psychostimulant drug (fenozolone)]. (Article in French). Rev Neuropsychiatr Infant, 20(6):615-8.
• [13] Loubinoux, I., Boulanouar, K., Ranjeva, J.P., Carel, C., Berry, I., Rascol, O., Celsis, P., Chollet, F. (1999). Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J Cereb Blood Flow Metab, 19(12):1365-75.
• [14] Gielsdorf, W. (1982). Determination of the psychostimulants pemoline, fenozolone and thozalinone in human urine by gas chromatography/mass spectrometry and thin layer chromatography. J Clin Chem Clin Biochem, 20(2):65-8.
• [15]  Les Laboratoires Dausse. 5-phenyl-2-ethylamino-4-oxazolinone and its preparation. Les Laboratoires Dausse, assignee. Patent GB963375A. 23 Feb. 1962.
• [16] VirualToxLab 5.8 Results. (2016). Biograf3R. [online]. Available at: http://www.biograf.ch/data/projects/virtualtoxlab_results.php [Accessed 3 October, 2018]