Roxindole

Roxindole

Clinical data
Other names	EMD-49980; EMD49980
ATC code	None
Identifiers
IUPAC name 3-[4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)butyl]-1H-indol-5-ol
CAS Number	112192-04-8
PubChem CID	219050
IUPHAR/BPS	52
ChemSpider	189880
UNII	43227SMS0O
CompTox Dashboard (EPA)	DTXSID5043895
Chemical and physical data
Formula	C23H26N2O
Molar mass	346.474 g·mol−1
3D model (JSmol)	Interactive image
SMILES Oc1ccc2c(c1)c(c[nH]2)CCCCN4C/C=C(/c3ccccc3)CC4

Roxindole (developmental code name EMD-49980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. ^{[1] [2] [3]} In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. ^{[2] [3]} As a result, roxindole was further researched for the treatment of depression instead. ^{[1] [4]} It has also been investigated as a therapy for Parkinson's disease and prolactinoma. ^{[5] [6]} However, it has never been marketed. ^[7]

Roxindole acts as an agonist at the following receptors: ^{[8] [9]}

• D₂ receptor (K_i = 2.82 nM)
• D₃ receptor (K_i = 1.17 nM)
• D₄ receptor (K_i = 5.89 nM)
• 5-HT_1A receptor (K_i = 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. ^{[10] [11]} Weaker activity at the serotonin 1_B and 1_D receptors has been seen. ^[12] It is also a serotonin reuptake inhibitor (IC₅₀ = 1.4 nM) and has been reported to act as a 5-HT_2A receptor antagonist as well. ^{[9] [10] [11] [13]}

References

1. Gründer G, Wetzel H, Hammes E, Benkert O (1993). "Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression". Psychopharmacology. 111 (1): 123–126. doi:10.1007/BF02257418. PMID   7870927. S2CID   8154586.
2. Klimke A, Klieser E (July 1991). "Antipsychotic efficacy of the dopaminergic autoreceptor agonist EMD 49980 (Roxindol). Results of an open clinical study". Pharmacopsychiatry. 24 (4): 107–112. doi:10.1055/s-2007-1014451. PMID   1684439.
3. Kasper S, Fuger J, Zinner HJ, Bäuml J, Möller HJ (March 1992). "Early clinical results with the neuroleptic roxindole (EMD 49,980) in the treatment of schizophrenia--an open study". European Neuropsychopharmacology. 2 (1): 91–95. doi:10.1016/0924-977X(92)90041-6. PMID   1353388. S2CID   21861347.
4. Maj J, Kolodziejczyk K, Rogóz Z, Skuza G (1996). "Roxindole, a potential antidepressant. I. Effect on the dopamine system". Journal of Neural Transmission. 103 (5): 627–641. doi:10.1007/bf01273159. PMID   8811507. S2CID   33701841.
5. Bravi D, Davis TL, Mouradian MM, Chase TN (April 1993). "Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980". Movement Disorders. 8 (2): 195–197. doi:10.1002/mds.870080214. PMID   8097280. S2CID   23676084.
6. Jaspers C, Benker G, Reinwein D (June 1994). "Treatment of prolactinoma patients with the new non-ergot dopamine agonist roxindol: first results". The Clinical Investigator. 72 (6): 451–456. doi:10.1007/bf00180520. PMID   7950157. S2CID   532184.
7. Elks, J. (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 1083. ISBN   978-1-4757-2085-3 . Retrieved 2 February 2025.
8. Newman-Tancredi A, Cussac D, Audinot V, Millan MJ (June 1999). "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. doi:10.1007/pl00005374. PMID   10431754. S2CID   19721911. Archived from the original on 2013-02-11.
9. Heinrich T, Böttcher H, Bartoszyk GD, Greiner HE, Seyfried CA, Van Amsterdam C (September 2004). "Indolebutylamines as selective 5-HT(1A) agonists". Journal of Medicinal Chemistry. 47 (19): 4677–4683. doi:10.1021/jm040792y. PMID   15341483.
10. Seyfried CA, Greiner HE, Haase AF (January 1989). "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. doi:10.1016/0014-2999(89)90651-1. PMID   2565817.
11. Bartoszyk GD, Harting J, Minck KO (January 1996). "Roxindole: psychopharmacological profile of a dopamine D2 autoreceptor agonist". The Journal of Pharmacology and Experimental Therapeutics. 276 (1): 41–48. PMID   8558454.
12. Newman-Tancredi A, Cussac D, Audinot V, Millan MJ (June 1999). "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. doi:10.1007/pl00005374. PMID   10431754. S2CID   19721911.
13. Maj J, Kołodziejczyk K, Rogóz Z, Skuza G (March 1997). "Roxindole, a dopamine autoreceptor agonist with a potential antidepressant activity. II. Effects on the 5-hydroxytryptamine system". Pharmacopsychiatry. 30 (2): 55–61. doi:10.1055/s-2007-979483. PMID   9131725.