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 It is no longer used due mainly to safety concerns, as it has a serotonergic effects profile similar to other withdrawn appetite suppressants such as fenfluramine and aminorex which were found to cause pulmonary hypertension and cardiac fibrosis following prolonged use.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

Monoamine release of chlorphentermine and related agents (EC50 Tooltip Half maximal effective concentration, nM)
Compound NE Tooltip Norepinephrine DA Tooltip Dopamine 5-HT Tooltip SerotoninRef
Phenethylamine 10.939.5>10,000 [15] [16] [17]
Dextroamphetamine 6.6–7.25.8–24.8698–1,765 [18] [19]
para-Chloroamphetamine 23.5–26.242.2–68.528.3 [16] [17] [20] [21]
Phentermine 28.8–39.42622,575–3,511 [18] [17] [22]
Chlorphentermine >10,000 (RI)935–2,65018.2–30.9 [18] [22]
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assay was done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: [23] [24]

Chlorphentermine acts as a selective serotonin releasing agent (SSRA). [25] [26] [18] 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. [25] [26] [18] 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). [27] [26] The activity of chlorphentermine as an SSRA is in contrast to phentermine, which acts as a selective norepinephrine and dopamine releasing agent (NDRA). [26] [18]

In animals, chlorphentermine robustly and dose-dependently increases serotonin levels in the brain. [23] [14] It also increases dopamine levels in the brain at high doses. [23] [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. [28] [13] [14] Conversely, it has been reported that chlorphentermine weakly stimulates locomotor activity at low doses and progressively suppresses it at higher doses. [29] In contrast to other amphetamines, it does not produce stereotypies nor reverse reserpine-induced behavioral depression. [29] In addition, unlike para-chloroamphetamine (PCA), chlorphentermine does not produce the head-twitch response, a behavioral proxy of psychedelic effects, in animals. [29]

In contrast to fenfluramine and norfenfluramine, chlorphentermine shows negligible activity as an agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [26] Its EC50 values at these receptors are >10,000 nM, 5,370 nM, and 6,456 nM, respectively. [26] These EC50 values are >324-fold, 164-fold, and 209-fold lower than its EC50 value in inducing serotonin release, respectively. [26]

Despite its lack of direct agonism at the serotonin 5-HT2B receptors, chlorphentermine shows induction of primary pulmonary hypertension in animal models. [26] [3] This suggests that serotonin release can induce this form of toxicity without concomitant direct serotonin 5-HT2B receptor agonism. [26] 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. [30] 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. [26]

The amphetamine homologue of chlorphentermine, PCA, is a potent serotonergic neurotoxin. [31] In contrast to PCA, preliminary animal experiments suggest that chlorphentermine is non-neurotoxic, although more research in this area is still needed. [31]

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. [23] It is the para-chloro analogue of phentermine. [23] 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. [32]

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 [33] 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] [34] 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</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 Adipex-P among others, is a medication used together with diet and exercise to treat obesity. It is available by itself or as the combination phentermine/topiramate. Phentermine is taken by mouth.

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

Phenmetrazine, sold under the brand name Preludin among others, is a stimulant drug first synthesized in 1952 and originally used as an appetite suppressant, but withdrawn from the market in the 1980s due to widespread misuse. It was initially replaced by its analogue phendimetrazine which functions as a prodrug to phenmetrazine, but now it is rarely prescribed, due to concerns of misuse and addiction. Chemically, phenmetrazine is a substituted amphetamine containing a morpholine ring or a substituted phenylmorpholine.

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

Aminorex, sold under the brand names Menocil and Apiquel among others, is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension (PPH). In the United States, aminorex is a Schedule I controlled substance.

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

Etilamfetamine, also known as N-ethylamphetamine and formerly sold under the brand names Apetinil and Adiparthrol, is a stimulant drug of the amphetamine family. 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.

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

Naphthylaminopropane, also known as naphthylisopropylamine (NIPA), is an experimental drug that was under investigation for the treatment of alcohol and stimulant addiction.

<span class="mw-page-title-main">Norfenfluramine</span> Never-marketed drug of the amphetamine family

Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family and a major active metabolite of the appetite suppressants fenfluramine and benfluorex. The compound is a racemic mixture of two enantiomers with differing activities, dexnorfenfluramine and levonorfenfluramine.

<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 one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

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

<span class="mw-page-title-main">Dopamine releasing agent</span> Type of drug

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 (4-MA), also known by the former proposed brand name Aptrol, is a stimulant and anorectic drug of the amphetamine family. It is structurally related to mephedrone (4-methylmethcathinone).

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

4-Methylmethamphetamine (4-MMA), also known as mephedrine, is a putative stimulant and entactogen drug of the amphetamine family. It acts as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). The drug is the β-deketo analogue of mephedrone and the N-methyl analogue of 4-methylamphetamine (4-MA).

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

Levofenfluramine (INN), or (−)-3-trifluoromethyl-N-ethylamphetamine, also known as (−)-fenfluramine or (R)-fenfluramine, is a drug of the amphetamine family that, itself (i.e., in enantiopure form), was never marketed. It is the levorotatory enantiomer of fenfluramine, the racemic form of the compound, whereas the dextrorotatory enantiomer is dexfenfluramine. Both fenfluramine and dexfenfluramine are anorectic agents that have been used clinically in the treatment of obesity (and hence, levofenfluramine has been as well since it is a component of fenfluramine). However, they have since been discontinued due to reports of causing cardiovascular conditions such as valvular heart disease and pulmonary hypertension, adverse effects that are likely to be caused by excessive stimulation of 5-HT2B receptors expressed on heart valves.

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

Pseudophenmetrazine is a psychostimulant of the phenylmorpholine group. It is the N-demethylated and cis-configured analogue of phendimetrazine as well as the cis-configured stereoisomer of phenmetrazine. In addition, along with phenmetrazine, it is believed to be one of the active metabolites of phendimetrazine, which itself is inactive and behaves merely as a prodrug.

<span class="mw-page-title-main">4,4'-Dimethylaminorex</span> Chemical compound

4,4'-Dimethylaminorex, sometimes referred to by the street name "Serotoni", is a psychostimulant and entactogen designer drug related to aminorex, 4-methylaminorex, and pemoline. It was first detected in the Netherlands in December 2012, and has been sold as a designer drug around Europe since mid-2013.

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

Methamnetamine is a triple monoamine releasing agent and N-methyl analog of the non-neurotoxic experimental drug naphthylaminopropane and the naphthalene analog of methamphetamine. It has been sold online as a designer drug.

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

3',4'-Methylenedioxy-4-methylaminorex (MDMAR) is a recreational designer drug from the substituted aminorex family, with monoamine-releasing effects. It is a potent serotonin–norepinephrine–dopamine releasing agent (SNDRA).

<span class="mw-page-title-main">BMAPN</span> Substituted cathinone stimulant drug

BMAPN, also known as βk-methamnetamine or as 2-naphthylmethcathinone, is a substituted cathinone derivative with stimulant effects. It inhibits dopamine reuptake and has rewarding and reinforcing properties in animal studies. It is banned under drug analogue legislation in a number of jurisdictions. The drug was at one point marketed under the name NRG-3, although only a minority of samples of substances sold under this name have been found to actually contain BMAPN, with most such samples containing mixtures of other cathinone derivatives.

<span class="mw-page-title-main">Ethylnaphthylaminopropane</span> Pharmaceutical compound

Ethylnaphthylaminopropane is a monoamine releasing agent (MRA) of the amphetamine family that is related to naphthylaminopropane and methamnetamine. It acts specifically as a serotonin–norepinephrine–dopamine releasing agent (SNDRA). However, ENAP is unusual in being a partial releaser of serotonin and dopamine and a full releaser of norepinephrine.

<span class="mw-page-title-main">Naphthylmetrazine</span> Pharmaceutical compound

Naphthylmetrazine, also known as 3-methyl-2-(2′-naphthyl)morpholine, is a monoamine releasing agent (MRA) and monoamine reuptake inhibitor (MRI) of the phenylmorpholine family related to phenmetrazine. It is the analogue of phenmetrazine in which the phenyl ring has been replaced with a naphthalene ring.

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.
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  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.
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  18. 1 2 3 4 5 6 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.
  19. ↑ Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (2013). "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology. 38 (4): 552–562. doi:10.1038/npp.2012.204. PMC   3572453 . PMID   23072836.
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  21. ↑ Nicole L (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. Retrieved 5 December 2024. FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
  22. 1 2 Partilla JS, Dersch CM, Baumann MH, Carroll FI, Rothman RB (1999). "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substractes". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc (PDF). NIDA Res Monogr. Vol. 180. pp. 1–476 (252). PMID   11680410. RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). [...] Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). [...]
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  27. ↑ 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.
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  30. ↑ 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.
  31. 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.
  32. ↑ Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6.
  33. ↑ 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.
  34. ↑ 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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