Chlorphentermine Explained

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).[1] 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 It is no longer used due mainly to safety concerns, as it has a serotonergic effects profile similar to other withdrawn appetite suppressants such as fenfluramine and aminorex which were found to cause pulmonary hypertension and cardiac fibrosis following prolonged use.[2]

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.[3] [4]

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[5] [6] 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).[7] The for monoamine release with chlorphentermine are 30.9nM for serotonin, >10,000nM for norepinephrine, and 2,650nM for dopamine.[8] [9] 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).[10] 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.[11] 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.[12]

In contrast to fenfluramine and norfenfluramine, chlorphentermine shows negligible activity as an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C 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-HT2B 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-HT2B 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-HT2B receptor agonism in this toxicity.[13] It has been said that it is possible that an active metabolite of chlorphentermine might show greater serotonin 5-HT2B 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, para-chloroamphetamine (PCA), is a potent serotonergic neurotoxin.[14] 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.[15]

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.[16]

History

Chlorphentermine was first described in the scientific literature by 1954.[17] [18] [19] [20] 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[21] 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.[22] [23] Pulmonary toxicity of chlorphentermine was observed in animals by the early 1970s and this resulted in reservations about its clinical use.

Notes and References

  1. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS . Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin . Synapse . 39 . 1 . 32–41 . January 2001 . 11071707 . 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 . 15573624 .
  2. Rothman RB, Ayestas MA, Dersch CM, Baumann MH . Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension . Circulation . 100 . 8 . 869–875 . August 1999 . 10458725 . 10.1161/01.cir.100.8.869 . free .
  3. Court JM . The management of obesity . Drugs . 4 . 5 . 411–418 . 1972 . 4568066 . 10.2165/00003495-197204050-00003 .
  4. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms . Springer Netherlands . 2012 . 978-94-011-4439-1 . 4 November 2024 . 74.
  5. Rothman RB, Baumann MH . Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs . Annals of the New York Academy of Sciences . 1074 . 1. 245–260 . August 2006 . 17105921 . 10.1196/annals.1369.064 . 2006NYASA1074..245R .
  6. Baumann MH, Ayestas MA, Dersch CM, Brockington A, Rice KC, Rothman RB . Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications . Synapse . 36 . 2 . 102–113 . May 2000 . 10767057 . 10.1002/(SICI)1098-2396(200005)36:2<102::AID-SYN3>3.0.CO;2-# .
  7. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS . Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin . Synapse . 39 . 1 . 32–41 . January 2001 . 11071707 . 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 .
  8. Rothman RB, Baumann MH . Therapeutic and adverse actions of serotonin transporter substrates . Pharmacology & Therapeutics . 95 . 1 . 73–88 . July 2002 . 12163129 . 10.1016/s0163-7258(02)00234-6 .
  9. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Current Topics in Medicinal Chemistry . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .
  10. Rothman RB, Baumann MH . Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects . Drug Development Research . Wiley . 51 . 2 . 2000 . 0272-4391 . 10.1002/1098-2299(200010)51:2<52::aid-ddr2>3.0.co;2-h . 52–65.
  11. Rothman RB, Baumann MH . Monoamine transporters and psychostimulant drugs . European Journal of Pharmacology . 479 . 1–3 . 23–40 . October 2003 . 14612135 . 10.1016/j.ejphar.2003.08.054 .
  12. Rothman RB, Blough BE, Baumann MH . Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction . Trends in Pharmacological Sciences . 27 . 12 . 612–618 . December 2006 . 17056126 . 10.1016/j.tips.2006.10.006 .
  13. Zolkowska D, Baumann MH, Rothman RB . Chronic fenfluramine administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels . The Journal of Pharmacology and Experimental Therapeutics . 324 . 2 . 791–797 . February 2008 . 18032571 . 10.1124/jpet.107.132654 .
  14. Lovenberg W, Walker MN, Baumgarten HG . Chlorinated amphetamines: drugs or toxins . Monographs in Neural Sciences . Frontiers of Neurology and Neuroscience . 3 . 109–114 . 1976 . 790166 . 10.1159/000399342 . 978-3-8055-2328-8 . A methylated analogue of p-chloroamphetamine is chlorphentermine (fig. 1). This compound is marketed as an appetite suppressant Pre-Sate® and it seemed of interest to reevaluate the effects of this compound on the serotonergic system. One day following the administration of 20 mg/kg to rats there appeared to be little loss of tryptophan hydroxylase in any of the brain regions; e.g., mesencephalic tegmentum 124 %, mesencephalic tectum 95.7 % and striatum 103.5 %, of control values. While this preliminary experiment would suggest that chlorphentermine is not neurotoxic, it would seem in view of the similarity of its structure to p-chloroamphetamine that considerably more detailed experiments should be done to evaluate the long-term effects of this drug and its potential neurotoxicity. .
  15. Craddock D . Anorectic drugs: use in general practice . Drugs . 11 . 5 . 378–393 . 1976 . 782835 . 10.2165/00003495-197611050-00002 . 25704474 .
  16. Book: Shulgin AT . Stimulants . Psychotomimetic Drugs: Structure-Activity Relationships . Springer US . Boston, MA . 1978 . 978-1-4757-0512-6 . 10.1007/978-1-4757-0510-2_6 . 243–333.
  17. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies . Springer US . 2014 . 978-1-4757-2085-3 . 3 November 2024 . 264.
  18. Gylys JA, Hart JJ, Warren MR . Chlorphentermine, a new anorectic agent . The Journal of Pharmacology and Experimental Therapeutics . 137 . 365–373 . September 1962 . 13903304 .
  19. Lucey C, Hadden DR . Chlorphentermine: a new "appetite suppressant". A cross-over double-blind trial . The Ulster Medical Journal . 31 . 2 . 181–184 . December 1962 . 13931448 . 2384794 .
  20. Fineberg SK . Evaluation of Anorexigenic Agents . The American Journal of Clinical Nutrition . Elsevier BV . 11 . 5 . 1962 . 0002-9165 . 10.1093/ajcn/11.5.509 . free . 509–516.
  21. Bazan IS, Fares WH . Review of the Ongoing Story of Appetite Suppressants, Serotonin Pathway, and Pulmonary Vascular Disease . The American Journal of Cardiology . 117 . 10 . 1691–1696 . May 2016 . 27018933 . 10.1016/j.amjcard.2016.02.049 .
  22. Book: Schweizerischer Apotheker-Verein . Index Nominum: International Drug Directory . Medpharm Scientific Publishers . 2004 . 978-3-88763-101-7 . 3 November 2024 . 258.
  23. Book: Schweizerischer Apotheker-Verein . Index Nominum 2000: International Drug Directory . Medpharm Scientific Publishers . 2000 . 978-3-88763-075-1 . 3 November 2024 . 222.

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