Thozalinone, ≥98%

Chemical Information:

Technical Information:

Background:

Thozalinone (N,N-Dimethylpemoline) is an approximately 1.5x - 2x more potent derivative of Pemoline, described as showing "better properties than [Pemoline]."[1]

Pemoline itself is a stimulant drug of the 4-oxazolidinone class, that was used to treat attention deficit hyperactivity disorder (ADHD) but was later withdrawn from the market due to severe liver toxicity in some people.[2] There have been no reported cases of hepatotoxicity in studies with Thozalinone, although it has not been sold on the market as a pharmaceutical.

Thozalinone has been described as belonging to a class of "excitants with unique properties distinguishing them from the sympathomimetic amines."⁷ In the past, Thozalinone has been used in studies for the potential treatment of depression, obesity, attention deficit disorder, and Parkinson’s disease.[3] According to the original patent:

“Thozalinone, as opposed to dextro-amphetamine, causes a marked increase in the synthesis of dopamine in the brain. Thozalinone is thus superior to dextro-amphetamine which has been used for the treatment of Parkinson's disease.”[4]

“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.” [7]

Modes of action:

The detailed mechanism of action for Thozalinone has not yet been fully elucidated. However, research it has be used in several clinical trials investigating its potential for use in the treatment of depression [5] and obesity [6], and was described as "most interesting", because of its "potency, safety, and duration of action"[7].

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.” [7]

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:

Due to a relative lack of research on the compound, no meta studies or literature reviews have been conducted, to-date.

Human studies:

Thozalinone has been studied in several clinical trials. For example, in 1971, researchers studied its efficacy for weight loss in obese patients.[8] 

In 1966, the potential antidepressant effects of Thozalinone were studied in a double-blind trial on depressed patients.[9]

Animal studies:

In 1967, the comparative interaction effects of amphetamine, alpha-pipradrol, methylphenidate and thozalinone with imipramine or desmethylimipramine were studied in rats. The results showed that the combination of thozalinone and the imipramines produced neither enhancement, nor prolongation, of the effects of Thozalinone – indicating that the drug is in a unique class of its own.[10]

In 1980, the effects of thozalinone on the sensitivity of dopaminergic receptors in mice was studied. Mice were fed daily doses of neuroleptic drugs (haloperidol, clozapine, chlorpromazine, trifluoperazine, or thioridazine) for 2, 4, or 8 weeks. Subsequently, they were treated with Thozalinone. Alcohol increased the Thozalinone-elicited gnawing behavior.[11]

A similar study was performed in 1985, when researchers tested the effects of several neuroleptic drugs on the inhibition of dopaminergic agonist-induced gnawing behavior in mice. Dopaminergic agonists tent to cause gnawing or biting behavior in rodents. Five drugs, including Thozalinone, were tested and the criterion for blocking effectiveness was the prevention of the biting or gnawing behavior. Prevention indexes (PI) were calculated from the LD₅₀/ED₅₀. Another selective index (SI) of each drug was established by the ED₅₀/ND₅₀ ratio. Overall, SI data for the Thozalinone test provided the best prediction.[12]

In the early 1960s, researchers published some interesting information comparing Thozalinone to amphetamine. [7] Their findings looked promising and are explained below. For example, Thozalinone was found to be  approximately one-third as potent as amphetamine by weight when administered orally in mice. However, it was only approximately one-sixth to one-tenth as toxic as amphetamine administered orally and, in contrast to Amphetamine, Thozalinone did not cause tremors or convulsions.

Thozalinone showed no evidence of tolerance to its effects when administered to rats orally for 11 consecutive days, and increased locomotor activity and exploratory behavior in mice with a rapid onset, for longer than 8 hours. Thozalinone was effective in dosages from 7.5mg/kg up to 960 mg/kg, before showing disruptive toxicity. Amphetamine produced similar effects, but with a longer onset time, and a shorter duration than Thozalinone in mice.

Thozalinone did not affect the temperature of mice when administered from 30 mg/kg up to 120 mg/kg orally, while amphetamine significantly elevated the temperature of mice when administered at similar dosages. Thozalinone (15+ mg/kg orally) and Amphetamine (10+ mg/kg orally) were both able to reduce Reserpine induced sedation. Thozalinone (2+ mg/kg IP) and Amphetamine (1+ mg/kg IP) were both able to prevent Tetrabenazine induced depression.

Thozalinone increased locomotor activity and increased exploratory behavior from 2 mg/kg up to 64 mg/kg orally in rats. It also produced excitation in cats, at 10 mg/kg - 20 mg/kg, orally and this excitation was marked and lasted for >7 hours.

At toxic dosages (500 mg/kg+), Thozalinone did not produce ataxia, hyperesthesia, change in respiration, nor convulsions. Amphetamine, at much lower toxic doses caused tachycardia, hypertension, hyperventilation, tremors and convulsions. Thozalinone did not exhibit MAO inhibition at a concentration of 0.15 mg/mL (approximately 10^-3 M). Thozalinone was more effective than Amphetamine at decreasing food consumption over a 6-hour period.

 Thozalinone produced excitement and mydriasis in dogs 10 mg/kg orally which lasted as long as 8 hours. Thozalinone showed no significant changes in arterial blood pressure or heart rate in rats (35mg/kg orally) and, similarly, had no effect on blood pressure or heart rate in dogs. Thozalinone caused no side effects or overt changes in behavior when administered intravenously to the dogs.

It was concluded on the basis of the above research that Thozalinone had a unique profile which was partly similar to mood-elevating and euphoric stimulants such as the sympathomimetic amines, yet also showed similarity to other classes of antidepressants including deanol, due to having a high therapeutic index and no cardiovascular side effects. Thozalinone was described as causing "increased purposeful behavior" in mice, and causing similar excitement in rats, cats, and dogs as amphetamine, but without increasing blood pressure or leading to other adverse sympathomimetic effects.

Toxicity Cases:

There have been no reported toxicity cases for this compound. 

References:

• [1] Howell, C.F., Quinones, N.Q., & Hardy, R.A. (1962). 2-Amino-2-oxazolin-4-ones. I. Synthesis. The Journal of Organic Chemistry 27, no. 5 1679-685.
• [2] Pemoline – withdrawn due to liver toxicity risk. (2005). In: WHO Pharmaceuticals Newsletter, No. 5. World Health Organization (WHO).
• [3] Thozalinone – Compound Summary for CID 12602. PubChem, Open Chemistry Database. Available online from https://pubchem.ncbi.nlm.nih.gov/compound/thozalinone [Accessed 10 October, 2018].
• [4] Gray, W.D., Rauh, C.E. (1972). Thozalinone as an Anti-Parkinson Agent. United States Patent 3665075. American Cyanamid Company (Stamford, CT).
• [5] 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.
• [6] 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.
• [7] Greenblatt, E.N., Osterberg, A.C. (1965). Some pharmacologic properties of thozalinone, a new excitant. Toxicol Appl Pharmacol, 7(4):566-78.
• [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] 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.
• [10] Bernard, M. Bernstein, C.N. (1968). Latimer Behavioral facilitation: The interaction of imipramine and desipramine with amphetamine, alpha-pipradrol, methylphenidate, and thozalinone. Psychopharmacologia, 12(4): 338-345
   
• [11] Yen-koo, H. C., & Balazs, T. (1980). Detection of Dopaminergic Supersensitivity Induced by Neuroleptic Drugs in Mice. Drug and Chemical Toxicology, 3(2), 237–247.
• [12] Yen-Koo, H.C., Davis, D.A., Balazs, T. (1985). Inhibition of dopaminergic agonist-induced gnawing behavior by neuroleptic drugs in mice. Drug Chem Toxicol; 8(6):495-502.