7-Chlorolorcaserin

Last updated

7-Chlorolorcaserin
7-Chlorolorcaserin.svg
Clinical data
Other names7-Cl-lorcaserin
Drug class Serotonin 5-HT2 receptor agonist
ATC code
  • None
Identifiers
  • (1R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C11H13Cl2N
Molar mass 230.13 g·mol−1
3D model (JSmol)
  • C[C@H]1CNCCC2=CC(=C(C=C12)Cl)Cl
  • InChI=1S/C11H13Cl2N/c1-7-6-14-3-2-8-4-10(12)11(13)5-9(7)8/h4-5,7,14H,2-3,6H2,1H3/t7-/m0/s1
  • Key:KTCVEIAEKPSBCJ-ZETCQYMHSA-N

7-Chlorolorcaserin, also known as (1R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, is a serotonin 5-HT2 receptor agonist of the 3-benzazepine family related to the previously marketed appetite suppressant and anti-obesity drug lorcaserin (Belviq). [1] [2] It is specifically the 7-chloro derivative of lorcaserin. [1] [2] The drug is much more potent as a serotonin 5-HT2A receptor agonist and much less selective for the serotonin 5-HT2C receptor than lorcaserin. [1] [2] It was first described by 2005. [1] [2]

Contents

Pharmacology

Pharmacodynamics

7-Chlorolorcaserin is a potent agonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. [1] [2] Its EC50 Tooltip half-maximal effective concentration values were 10 nM at the serotonin 5-HT2A receptor, 40 nM at the serotonin 5-HT2B receptor, and 4.0 nM at the serotonin 5-HT2C receptor. [2] As such, the drug only showed about 2.5-fold selectivity for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor. [1] [2] It was the most potent serotonin 5-HT2A receptor agonist and among the most potent serotonin 5-HT2C receptor agonists of a large series of evaluated 3-benzazepines. [2] Compared to lorcaserin, 7-chlorolorcaserin was about 16-fold more potent as a serotonin 5-HT2A receptor agonist and about twice as potent as a serotonin 5-HT2C receptor agonist. [2] Relatedly, it was much less selective for the serotonin 5-HT2C receptor over the serotonin 5-HT2A receptor in comparison to lorcaserin, which itself showed about 20-fold selectivity. [2]

The drug was assessed in rodents and was found to produce appetite suppression similarly to but somewhat less potently than lorcaserin. [2] In addition to appetite suppression, lorcaserin has been found to produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. [3] [4] However, this occurs only when lorcaserin is administered in combination with a selective serotonin 5-HT2C receptor antagonist such as SB-242084. [3] [4] As a presumable result of serotonin 5-HT2A receptor activation, lorcaserin has likewise been found to produce hallucinogenic effects at several-fold supratherapeutic doses in humans. [3] This resulted in lorcaserin being designated a Schedule IV controlled substance in the United States. [5] Unlike lorcaserin, 7-chlorolorcaserin is not known to have been assessed in terms of psychedelic-related effects. [1] [2]

Chemistry

7-Chlorolorcaserin, also known as (1R)-7,8-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, is a substituted 3-benzazepine and the 7-chloro derivative of lorcaserin. [6] [1] [2] Both lorcaserin and 7-chlorolorcaserin are cyclized phenethylamines and may be thought of as cyclized analogues of amphetamine appetite suppressants like para-chloroamphetamine, chlorphentermine, and fenfluramine. [6] [1] [2]

7-Chlorolorcaserin is the (R)- enantiomer of a chiral compound and racemic mixture of (R)- and (S)- stereoisomers. [1] [2] The (S)- enantiomer and the racemic mixture are also potent serotonin 5-HT2 receptor agonists, but are less potent and more selective for the serotonin 5-HT2C receptor than 7-chlorolorcaserin. [1] [2] Lorcaserin is an enantiopure (R)- enantiomer similarly to 7-chlorolorcaserin. [1] [2]

Synthesis

The chemical synthesis of 7-chlorolorcaserin has been described. [2]

History

7-Chlorolorcaserin was described in the scientific literature by a large team at Arena Pharmaceuticals by 2005. [1] [2] Lorcaserin was selected for development instead due to its profile being most optimal as an appetite suppressant and 7-chlorolorcaserin was not further investigated. [1] [2] [7]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (March 2005). "Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity". Bioorganic & Medicinal Chemistry Letters. 15 (5): 1467–1470. doi:10.1016/j.bmcl.2004.12.080. PMID   15713408.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, et al. (January 2008). "Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity". Journal of Medicinal Chemistry. 51 (2): 305–313. doi:10.1021/jm0709034. PMID   18095642.
  3. 1 2 3 Collins GT, Gerak LR, France CP (November 2018). "The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders". Neuropharmacology. 142: 63–71. doi:10.1016/j.neuropharm.2017.12.023. PMC   5997497 . PMID   29246856. [...] several lines of evidence suggest that lorcaserin also has actions at 5-HT2A receptors. First, in vitro functional studies suggest that lorcaserin is only modestly (~19-fold) selective for 5-HT2C over 5-HT2A receptors in vitro (Thomsen et al., 2008; also see Table 1), raising the possibility that the doses required to decrease intravenous drug self-administration are large enough to bind to and possibly exert effects at 5-HT2A receptors. Indeed, when evaluated in a sample of recreational polydrug users, doses only slightly larger (20-60 mg) than the maximally approved dose of 10 mg (administered twice daily [BID]) produced feelings of "high" and "bad effects", as well as perceptual changes that were described by a subset of subjects as "hallucination" and/or feeling "detached" and "spaced out" (Shram et al., 2011). Dose-dependent increases in other adverse effects (e.g., nausea, headache, dizziness, euphoric mood, etc.) were also noted, with most subjects (70-100%) reporting at least one adverse effect after receiving larger doses of lorcaserin (Shram et al., 2011).
  4. 1 2 Serafine KM, Rice KC, France CP (December 2015). "Directly Observable Behavioral Effects of Lorcaserin in Rats". The Journal of Pharmacology and Experimental Therapeutics. 355 (3): 381–385. doi:10.1124/jpet.115.228148. PMC   4658489 . PMID   26384326. When administered alone, lorcaserin did not produce head twitching; however, lorcaserin significantly increased head twitching in rats that were pretreated with the 5-HT2C receptor selective antagonist SB 242084. Drugs with agonist activity at 5-HT2A receptors increase head twitching (Canal and Morgan, 2012). [...] When administered alone up to a cumulative dose of 32.0 mg/kg, lorcaserin did not induce head twitching; these data are consistent with a previous report (Thomsen et al., 2008) in which lorcaserin administered via oral gavage did not share behavioral effects with the prototypic 5-HT2A receptor selective agonist DOI (e.g., wet dog shakes and back contractions). [...] Lorcaserin did not produce head twitching when administered alone, although it attenuated head twitching produced by the 5-HT2A receptor selective agonist DOM. [...]
  5. ↑ Tchang BG, Abel B, Zecca C, Saunders KH, Shukla AP (January 2020). "An up-to-date evaluation of lorcaserin hydrochloride for the treatment of obesity". Expert Opinion on Pharmacotherapy. 21 (1): 21–28. doi:10.1080/14656566.2019.1685496. PMID   31693425. Lorcaserin was approved by the FDA in 2012 as an adjunct to lifestyle changes for chronic weight management in adults with BMI≥30 kg/m2 or BMI≥27 kg/m2 with at least one weight-related comorbidity. It is delineated as a Schedule IV controlled substance because supratherapeutic doses of oral lorcaserin (40 and 60 mg) produced measures of euphoria and hallucinations in recreational drug users similar to positive controls zolpidem and ketamine. However, in clinical studies of participants with obesity treated for 4 weeks to 2 years, the incidence of euphoria and hallucinations following doses of lorcaserin up to 40 mg was less than 1% [9]. Short-term studies evaluating its abuse potential within 24 h demonstrated the negative effects of supratherapeutic doses starting at 40 mg [41].
  6. 1 2 "(5R)-7,8-dichloro-5-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine". PubChem. Retrieved 13 October 2025.
  7. ↑ Redman LM, Ravussin E (December 2010). "Lorcaserin for the treatment of obesity". Drugs of Today. 46 (12): 901–910. doi:10.1358/dot.2010.46.12.1556433. PMC   3773535 . PMID   21589947.
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