Chlorphentermine

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Chlorphentermine
Chlorphentermine.svg
Chlorphentermine molecule ball.png
Clinical data
Other names4-Chlorophentermine; 4-Chloro-α-methylamphetamine; 4-Chloro-α,α-dimethylphenethylamine
Routes of
administration 		Oral
Drug class Serotonin releasing agent; Selective serotonin releasing agent; Appetite suppressant; Anorectic; Anorexic; Anorexiant
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 40 hours [2] –5 days [3]
Identifiers
  • 1-(4-chlorophenyl)-2-methylpropan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.651 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H14ClN
Molar mass 183.68 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)CC(N)(C)C
  • InChI=1S/C10H14ClN/c1-10(2,12)7-8-3-5-9(11)6-4-8/h3-6H,7,12H2,1-2H3 Yes check.svgY
  • Key:ZCKAMNXUHHNZLN-UHFFFAOYSA-N Yes check.svgY
   (verify)

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.

Contents

The drug acts as a highly selective serotonin releasing agent (SRA). [4] 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 It is no longer used due mainly to safety concerns, as it has a serotonergic effects profile similar to other withdrawn appetite suppressants such as fenfluramine and aminorex which were found to cause pulmonary hypertension and cardiac fibrosis following prolonged use. [5]

Chlorphentermine was first synthesized by 1954 and was subsequently developed in the early 1960s. [6] [7] [8] [9] It remained on the market in the United States as late as 2004. [10]

Medical uses

Chlorphentermine was used as an appetite suppressant for purposes of weight loss in people with overweightness or obesity. [11] [3] [12]

Side effects

Side effects of chlorphentermine include impaired sleep, irritability, and gastrointestinal symptoms including dyspepsia. [11]

Euphoria is said to occasionally occur with chlorphentermine, but to a much lesser extent than with dextroamphetamine. [3] The drug does not produce amphetamine-like subjective effects in humans [13] [14] and the psychostimulant effects of chlorphentermine are described as much less than those of dextroamphetamine. [3]

Pharmacology

Pharmacodynamics

Chlorphentermine acts as a selective serotonin releasing agent (SSRA). [15] [16] [17] The EC50 Tooltip half-maximal effective concentration for monoamine release with chlorphentermine are 30.9 nM for serotonin, >10,000 nM for norepinephrine, and 2,650 nM for dopamine. [15] [16] [17] Although it is inactive as a norepinephrine releasing agent, it is a moderately potent norepinephrine reuptake inhibitor (IC50 Tooltip half-maximal inhibitory concentration = 451 nM; 15-fold lower than its EC50 value for serotonin release). [18] [16] The activity of chlorphentermine as an SSRA is in contrast to phentermine, which acts as a selective norepinephrine and dopamine releasing agent (NDRA). [16] [17]

In animals, chlorphentermine robustly and dose-dependently increases serotonin levels in the brain. [19] [14] It also increases dopamine levels in the brain at high doses. [19] [14] 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. [20] [13] [14]

In contrast to fenfluramine and norfenfluramine, chlorphentermine shows negligible activity as an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [16] Its EC50 values at these receptors are >10,000 nM, 5,370 nM, and 6,456 nM, respectively. [16] These EC50 values are >324-fold, 164-fold, and 209-fold lower than its EC50 value in inducing serotonin release, respectively. [16]

Despite its lack of direct agonism at the serotonin 5-HT2B receptors, chlorphentermine shows induction of primary pulmonary hypertension in animal models. [16] [3] This suggests that serotonin release can induce this form of toxicity without concomitant direct serotonin 5-HT2B receptor agonism. [16] 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. [21] 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. [16]

The amphetamine homologue of chlorphentermine, para-chloroamphetamine (PCA), is a potent serotonergic neurotoxin. [22] In contrast to PCA, preliminary animal experiments suggest that chlorphentermine is non-neurotoxic, although more research in this area is still needed. [22]

Pharmacokinetics

The elimination half-life of chlorphentermine is relatively long and is stated to be 40 hours [2] and about 5 days by different sources. [3]

Chemistry

Chlorphentermine, also known as 4-chlorophentermine, 4-chloro-α-methylamphetamine, and 4-chloro-α,α-dimethylphenethylamine, is a substituted phenethylamine and amphetamine derivative. [19] It is the para-chloro analogue of phentermine. [19] 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. [23]

History

Chlorphentermine was first described in the scientific literature by 1954. [6] [7] [8] [9] It was subsequently developed for use as an appetite suppressant in the early 1960s. [6] [7] [8] [9] The drug is said to have been withdrawn from the market in the United States in 1969 [24] and in the United Kingdom in 1974. [3] However, other sources indicate that chlorphentermine continued to be marketed in the United States as late as 2004. [10] [25] Pulmonary toxicity of chlorphentermine was observed in animals by the early 1970s and this resulted in reservations about its clinical use. [3]

Related Research Articles

<span class="mw-page-title-main">Fenfluramine/phentermine</span> Drug combination prescribed for weight loss; later withdrawn from market

The drug combination fenfluramine/phentermine, usually called fen-phen, is an anti-obesity medication that is no longer widely available. It was sold in the early 1990s, and utilized two anorectics. Fenfluramine was marketed by American Home Products as Pondimin, but was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal in 1997 and legal damages of over $13 billion. Phentermine was not shown to have harmful effects.

<span class="mw-page-title-main">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

α-Ethyltryptamine Chemical compound

α-Ethyltryptamine, also known as etryptamine, is an entactogen and stimulant drug of the tryptamine family. It was originally developed and marketed as an antidepressant under the brand name Monase by Upjohn in the 1960s before being withdrawn due to toxicity.

<span class="mw-page-title-main">Fenfluramine</span> Medication used to treat seizures

Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.

<span class="mw-page-title-main">Phentermine</span> Weight loss medication

Phentermine, sold under the brand name Ionamin among others, is a medication used together with diet and exercise to treat obesity. It is taken by mouth for up to a few weeks at a time, after which the benefits subside. It is also available as the combination phentermine/topiramate.

<span class="mw-page-title-main">Clortermine</span> Chemical compound

Clortermine (Voranil) was developed by Ciba in the 1960s and is an anorectic drug of the amphetamine class. It is the 2-chloro analogue of the better known appetite suppressant phentermine, and is the 2-chloro positional isomer of chlorphentermine. Clortermine produces very low rates of self-administration in animals similarly to chlorphentermine, and as a result it likely does not act on dopamine. Instead, it may act as a serotonin and/or norepinephrine releasing agent.

<span class="mw-page-title-main">Etilamfetamine</span> Chemical compound

Etilamfetamine is a stimulant drug of the phenethylamine and amphetamine chemical classes. It was invented in the early 20th century and was subsequently used as an anorectic or appetite suppressant in the 1950s, but was not as commonly used as other amphetamines such as amphetamine, methamphetamine, and benzphetamine, and was largely discontinued once newer drugs such as phenmetrazine were introduced. It most likely acts primarily as a dopamine releasing agent. Its activity as a norepinephrine or serotonin releasing agent is not known.

<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

Naphthylaminopropane (PAL-287) is an experimental drug under investigation as of 2007 for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">5-Fluoro-AMT</span> Chemical compound

5-Fluoro-α-methyltryptamine, also known as PAL-544, is a putative stimulant, entactogen, and psychedelic tryptamine derivative related to α-methyltryptamine (αMT). It has been found to act as a well-balanced serotonin-norepinephrine-dopamine releasing agent, a 5-HT2A receptor agonist, and a potent and specific MAO-A inhibitor. which suggests that 5-fluoro-αMT could be an active psychedelic in humans, although it is not known to have been tested in humans and could be dangerous due to its strong inhibition of MAO-A.

<i>para</i>-Chloroamphetamine Chemical compound

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a substituted amphetamine and monoamine releaser similar to MDMA, but with substantially higher activity as a monoaminergic neurotoxin, thought to be due to the unrestrained release of both serotonin and dopamine by a metabolite. It is used as a neurotoxin by neurobiologists to selectively kill serotonergic neurons for research purposes, in the same way that 6-hydroxydopamine is used to kill dopaminergic neurons.

<span class="mw-page-title-main">MDAI</span> Chemical compound

MDAI, also known as 5,6-methylenedioxy-2-aminoindane, is an entactogen drug of the 2-aminoindane group which is related to MDMA and produces similar subjective effects.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, including dopamine and norepinephrine neurons.

A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the body and/or brain.

<span class="mw-page-title-main">4-Methylamphetamine</span> Stimulant and anorectic drug of the amphetamine class

4-Methylamphetamine is a stimulant and anorectic drug of the phenethylamine and amphetamine chemical classes.

<span class="mw-page-title-main">3-Methylamphetamine</span> Stimulant drug of the amphetamine class

3-Methylamphetamine is a stimulant drug from the amphetamine family. It is self-administered by mice to a similar extent to 4-fluoroamphetamine and has comparable properties as a monoamine releaser, although with a more balanced release of all three monoamines, as opposed to the more dopamine/noradrenaline selective fluoro analogues.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Levofenfluramine</span> Non-marketed drug of the amphetamine class

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A release modulator, or neurotransmitter release modulator, is a type of drug that modulates the release of one or more neurotransmitters. Examples of release modulators include monoamine releasing agents such as the substituted amphetamines and release inhibitors such as botulinum toxin A.

(<i>R</i>)-MDMA Psychoactive drug taken by mouth

(R)-3,4-Methylenedioxy-N-methylamphetamine ((R)-MDMA), also known as (R)-midomafetamine or as levo-MDMA, is the (R)- or levorotatory (l-) enantiomer of 3,4-methylenedioxy-N-methylamphetamine (MDMA; midomafetamine; "ecstasy"), a racemic mixture of (R)-MDMA and (S)-MDMA. Like MDMA, (R)-MDMA is an entactogen or empathogen. It is taken by mouth.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. 1 2 "Chlorphentermine: Uses, Interactions, Mechanism of Action". DrugBank Online. 31 July 2007. Retrieved 4 November 2024.
  3. 1 2 3 4 5 6 7 8 Craddock D (1976). "Anorectic drugs: use in general practice". Drugs. 11 (5): 378–393. doi:10.2165/00003495-197611050-00002. PMID   782835. S2CID   25704474.
  4. ↑ Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707. S2CID   15573624.
  5. ↑ Rothman RB, Ayestas MA, Dersch CM, Baumann MH (August 1999). "Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension". Circulation. 100 (8): 869–875. doi: 10.1161/01.cir.100.8.869 . PMID   10458725.
  6. 1 2 3 Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 264. ISBN   978-1-4757-2085-3 . Retrieved 3 November 2024.
  7. 1 2 3 Gylys JA, Hart JJ, Warren MR (September 1962). "Chlorphentermine, a new anorectic agent". The Journal of Pharmacology and Experimental Therapeutics. 137: 365–373. PMID   13903304.
  8. 1 2 3 Lucey C, Hadden DR (December 1962). "Chlorphentermine: a new "appetite suppressant". A cross-over double-blind trial". The Ulster Medical Journal. 31 (2): 181–184. PMC   2384794 . PMID   13931448.
  9. 1 2 3 Fineberg SK (1962). "Evaluation of Anorexigenic Agents". The American Journal of Clinical Nutrition. 11 (5). Elsevier BV: 509–516. doi: 10.1093/ajcn/11.5.509 . ISSN   0002-9165.
  10. 1 2 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 258. ISBN   978-3-88763-101-7 . Retrieved 3 November 2024.
  11. 1 2 Court JM (1972). "The management of obesity". Drugs. 4 (5): 411–418. doi:10.2165/00003495-197204050-00003. PMID   4568066.
  12. ↑ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 74. ISBN   978-94-011-4439-1 . Retrieved 4 November 2024.
  13. 1 2 Rothman RB, Baumann MH (August 2006). "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. Bibcode:2006NYASA1074..245R. doi:10.1196/annals.1369.064. PMID   17105921.
  14. 1 2 3 4 Baumann MH, Ayestas MA, Dersch CM, Brockington A, Rice KC, Rothman RB (May 2000). "Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications". Synapse. 36 (2): 102–113. doi:10.1002/(SICI)1098-2396(200005)36:2<102::AID-SYN3>3.0.CO;2-#. PMID   10767057.
  15. 1 2 Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID   12163129.
  16. 1 2 3 4 5 6 7 8 9 10 Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID   17017961.
  17. 1 2 3 Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse. 39 (1): 32–41. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID   11071707.
  18. ↑ Rothman RB, Baumann MH (2000). "Neurochemical mechanisms of phentermine and fenfluramine: Therapeutic and adverse effects". Drug Development Research. 51 (2). Wiley: 52–65. doi:10.1002/1098-2299(200010)51:2<52::aid-ddr2>3.0.co;2-h. ISSN   0272-4391.
  19. 1 2 3 4 Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology. 479 (1–3): 23–40. doi:10.1016/j.ejphar.2003.08.054. PMID   14612135.
  20. ↑ Rothman RB, Blough BE, Baumann MH (December 2006). "Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction". Trends in Pharmacological Sciences. 27 (12): 612–618. doi:10.1016/j.tips.2006.10.006. PMID   17056126.
  21. ↑ Zolkowska D, Baumann MH, Rothman RB (February 2008). "Chronic fenfluramine administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels". The Journal of Pharmacology and Experimental Therapeutics. 324 (2): 791–797. doi:10.1124/jpet.107.132654. PMID   18032571.
  22. 1 2 Lovenberg W, Walker MN, Baumgarten HG (1976). "Chlorinated amphetamines: drugs or toxins". Monographs in Neural Sciences. Frontiers of Neurology and Neuroscience. 3: 109–114. doi:10.1159/000399342. ISBN   978-3-8055-2328-8. PMID   790166. 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.
  23. ↑ Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6.
  24. ↑ Bazan IS, Fares WH (May 2016). "Review of the Ongoing Story of Appetite Suppressants, Serotonin Pathway, and Pulmonary Vascular Disease". The American Journal of Cardiology. 117 (10): 1691–1696. doi:10.1016/j.amjcard.2016.02.049. PMID   27018933.
  25. ↑ Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 222. ISBN   978-3-88763-075-1 . Retrieved 3 November 2024.
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