Chemistry:Roxindole

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Roxindole (INN; developmental code name EMD-49980) is a dopaminergic and serotonergic drug which was under development for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), panic disorder, and psychotic disorders like schizophrenia but was never marketed.[1][2]

Pharmacology

Pharmacodynamics

Roxindole acts as an agonist at the following receptors:[3][4]

  • D2 receptor (Ki = 2.82 nM)
  • D3 receptor (Ki = 1.17 nM)
  • D4 receptor (Ki = 5.89 nM)
  • 5-HT1A receptor (Ki = 0.380 nM)

At D2 and possibly D3 receptors roxindole is a partial agonist with preferential actions at autoreceptors and has been touted as a 'selective' autoreceptor agonist, hence the justification of its application as an antipsychotic.[5][6] It shows markedly lower affinity for the serotonin 5-HT1B and 5-HT1D receptors and acts as a weak partial agonist of these receptors.[7] It is also a serotonin reuptake inhibitor (IC50 = 1.4 nM) and has been reported to act as a 5-HT2A receptor antagonist as well.[4][5][6][8]

History and development

Roxindole was originally developed by Merck KGaA for the treatment of schizophrenia.[9][10][11] In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects.[10][11] As a result, roxindole was further researched for the treatment of depression instead.[9][12] It has also been investigated as a therapy for Parkinson's disease and prolactinoma.[13][14] However, it has never been marketed.[15] The drug reached phase 3 clinical trials prior to the discontinuation of its development.[1][2]

See also

References

  1. ↑ 1.0 1.1 "Roxindole". 18 November 1997. https://adisinsight.springer.com/drugs/800001190. 
  2. ↑ 2.0 2.1 "Delving into the Latest Updates on Roxindole with Synapse". 8 May 2025. https://synapse.patsnap.com/drug/28b888104af9428694dc384fdee63f8d. 
  3. ↑ "Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 359 (6): 447–453. June 1999. doi:10.1007/pl00005374. PMID 10431754. http://link.springer.de/link/service/journals/00210/bibs/9359006/93590447.htm. 
  4. ↑ 4.0 4.1 "Indolebutylamines as selective 5-HT(1A) agonists". Journal of Medicinal Chemistry 47 (19): 4677–4683. September 2004. doi:10.1021/jm040792y. PMID 15341483. 
  5. ↑ 5.0 5.1 "Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems". European Journal of Pharmacology 160 (1): 31–41. January 1989. doi:10.1016/0014-2999(89)90651-1. PMID 2565817. 
  6. ↑ 6.0 6.1 "Roxindole: psychopharmacological profile of a dopamine D2 autoreceptor agonist". The Journal of Pharmacology and Experimental Therapeutics 276 (1): 41–48. January 1996. PMID 8558454. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8558454. 
  7. ↑ "Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 359 (6): 447–453. June 1999. doi:10.1007/pl00005374. PMID 10431754. 
  8. ↑ "Roxindole, a dopamine autoreceptor agonist with a potential antidepressant activity. II. Effects on the 5-hydroxytryptamine system". Pharmacopsychiatry 30 (2): 55–61. March 1997. doi:10.1055/s-2007-979483. PMID 9131725. 
  9. ↑ 9.0 9.1 "Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression". Psychopharmacology 111 (1): 123–126. 1993. doi:10.1007/BF02257418. PMID 7870927. 
  10. ↑ 10.0 10.1 "Antipsychotic efficacy of the dopaminergic autoreceptor agonist EMD 49980 (Roxindol). Results of an open clinical study". Pharmacopsychiatry 24 (4): 107–112. July 1991. doi:10.1055/s-2007-1014451. PMID 1684439. 
  11. ↑ 11.0 11.1 "Early clinical results with the neuroleptic roxindole (EMD 49,980) in the treatment of schizophrenia--an open study". European Neuropsychopharmacology 2 (1): 91–95. March 1992. doi:10.1016/0924-977X(92)90041-6. PMID 1353388. 
  12. ↑ "Roxindole, a potential antidepressant. I. Effect on the dopamine system". Journal of Neural Transmission 103 (5): 627–641. 1996. doi:10.1007/bf01273159. PMID 8811507. 
  13. ↑ "Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980". Movement Disorders 8 (2): 195–197. April 1993. doi:10.1002/mds.870080214. PMID 8097280. 
  14. ↑ "Treatment of prolactinoma patients with the new non-ergot dopamine agonist roxindol: first results". The Clinical Investigator 72 (6): 451–456. June 1994. doi:10.1007/bf00180520. PMID 7950157. 
  15. ↑ Elks, J. (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1083. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1083. Retrieved 2 February 2025. 



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