Chlorphentermine

Chlorphentermine, sold under the brand names Apsedon, Desopimon, and Lucofen, is a serotonergic appetite suppressant of the amphetamine family. Developed in 1962, it is the ''para''- chloro derivative of the better-known appetite suppressant phentermine, which is still in current use.

The drug acts as a highly selective serotonin releasing agent (SRA). It is not a psychostimulant and has little or no misuse potential, but is classed as a Schedule III drug in the United States due mainly to its similarity to other appetite suppressants such as diethylpropion which have been more widely misused. It is no longer used due mainly to safety concerns, as it has a serotonergic effects profile similar to other withdrawn appetite suppressants such as fenfluramine and aminorex which were found to cause pulmonary hypertension and cardiac fibrosis following prolonged use.

Chlorphentermine was first synthesized by 1954 and was subsequently developed in the early 1960s. It remained on the market in the United States as late as 2004.

Medical uses

Chlorphentermine was used as an appetite suppressant for purposes of weight loss in people with overweightness or obesity.

Side effects

Side effects of chlorphentermine include impaired sleep, irritability, and gastrointestinal symptoms including dyspepsia.

Euphoria is said to occasionally occur with chlorphentermine, but to a much lesser extent than with dextroamphetamine. The drug does not produce amphetamine-like subjective effects in humans and the psychostimulant effects of chlorphentermine are described as much less than those of dextroamphetamine.

Pharmacology

Pharmacodynamics

Chlorphentermine acts as a selective serotonin releasing agent (SSRA). The for monoamine release with chlorphentermine are 30.9nM for serotonin, >10,000nM for norepinephrine, and 2,650nM for dopamine. Although it is inactive as a norepinephrine releasing agent, it is a moderately potent norepinephrine reuptake inhibitor ( = 451nM; 15-fold lower than its value for serotonin release). The activity of chlorphentermine as an SSRA is in contrast to phentermine, which acts as a selective norepinephrine and dopamine releasing agent (NDRA).

In animals, chlorphentermine robustly and dose-dependently increases serotonin levels in the brain. It also increases dopamine levels in the brain at high doses. Whereas dextroamphetamine and phentermine robustly stimulate locomotor activity and are self-administered in animals, chlorphentermine does not increase locomotor activity and is either not self-administered or is only weakly self-administered. Conversely, it has been reported that chlorphentermine weakly stimulates locomotor activity at low doses and progressively suppresses it at higher doses. In contrast to other amphetamines, it does not produce stereotypies nor reverse reserpine-induced behavioral depression. In addition, unlike ''para''-chloroamphetamine (PCA), chlorphentermine does not produce the head-twitch response, a behavioral proxy of psychedelic effects, in animals.

In contrast to fenfluramine and norfenfluramine, chlorphentermine shows negligible activity as an agonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Its values at these receptors are >10,000nM, 5,370nM, and 6,456nM, respectively. These values are >324-fold, 164-fold, and 209-fold lower than its value in inducing serotonin release, respectively.

Despite its lack of direct agonism at the serotonin 5-HT_2B receptors, chlorphentermine shows induction of primary pulmonary hypertension in animal models. This suggests that serotonin release can induce this form of toxicity without concomitant direct serotonin 5-HT_2B receptor agonism. However, other findings seem to contradict this hypothesis, for instance increases in serotonin levels with fenfluramine and other serotonin-elevating drugs being inadequate for inducing cardiac valvulopathy-like changes, and instead implicating additional direct serotonin 5-HT_2B receptor agonism in this toxicity. It has been said that it is possible that an active metabolite of chlorphentermine might show greater serotonin 5-HT_2B receptor agonism than chlorphentermine itself, analogously to the case of fenfluramine and norfenfluramine, and that this possibility should be examined.

The amphetamine homologue of chlorphentermine, PCA, is a potent serotonergic neurotoxin. In contrast to PCA, preliminary animal experiments suggest that chlorphentermine is non-neurotoxic, although more research in this area is still needed.

Pharmacokinetics

The elimination half-life of chlorphentermine is relatively long and is stated to be 40hours and about 5days by different sources.

Chemistry

Chlorphentermine, also known as 4-chlorophentermine, 4-chloro-α-methylamphetamine, and 4-chloro-α,α-dimethylphenethylamine, is a substituted phenethylamine and amphetamine derivative. It is the ''para''- chloro analogue of phentermine. Chlorphentermine is also closely structurally related to certain other phentermines including cericlamine, cloforex, clortermine, etolorex, and methylenedioxyphentermine (MDPH). It is closely structurally related to the amphetamine derivatives ''para''-chloroamphetamine (PCA) and ''para''-chloromethamphetamine (PCMA) as well.

History

Chlorphentermine was first described in the scientific literature by 1954. It was subsequently developed for use as an appetite suppressant in the early 1960s. The drug is said to have been withdrawn from the market in the United States in 1969 and in the United Kingdom in 1974. However, other sources indicate that chlorphentermine continued to be marketed in the United States as late as 2004. Pulmonary toxicity of chlorphentermine was observed in animals by the early 1970s and this resulted in reservations about its clinical use.

References

{{Phenethylamines

4-Chlorophenyl compounds
Anorectics
Carbonic anhydrase activators
Cardiotoxins
Phentermines
Respiratory toxins
Serotonin releasing agents
Withdrawn drugs