Roxindole

{{Short description|Dopaminergic & serotonergic drug developed for schizophrenia treatment}}

{{Drugbox

| IUPAC_name = 3-[4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)butyl]-1H-indol-5-ol

| image = Roxindole.png

| width =

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| CAS_number = 112192-04-8

| ATC_prefix = None

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| PubChem = 219050

| IUPHAR_ligand = 52

| ChemSpiderID = 189880

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 43227SMS0O

| synonyms = EMD-49980; EMD49980

| C=23 | H=26 | N=2 | O=1

| 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.{{cite journal |vauthors=Gründer G, Wetzel H, Hammes E, Benkert O | title = Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression | journal = Psychopharmacology | volume = 111 | issue = 1 | pages = 123–126 | year = 1993 | pmid = 7870927 | doi = 10.1007/BF02257418| s2cid = 8154586 }}{{cite journal |vauthors=Klimke A, Klieser E | title = Antipsychotic efficacy of the dopaminergic autoreceptor agonist EMD 49980 (Roxindol). Results of an open clinical study | journal = Pharmacopsychiatry | volume = 24 | issue = 4 | pages = 107–112 |date=July 1991 | pmid = 1684439 | doi = 10.1055/s-2007-1014451}}{{cite journal |vauthors=Kasper S, Fuger J, Zinner HJ, Bäuml J, Möller HJ | title = Early clinical results with the neuroleptic roxindole (EMD 49,980) in the treatment of schizophrenia--an open study | journal = European Neuropsychopharmacology | volume = 2 | issue = 1 | pages = 91–95 |date=March 1992 | pmid = 1353388 | doi = 10.1016/0924-977X(92)90041-6| s2cid = 21861347 }} In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead.{{cite journal |vauthors=Maj J, Kolodziejczyk K, Rogóz Z, Skuza G | title = Roxindole, a potential antidepressant. I. Effect on the dopamine system | journal = Journal of Neural Transmission | volume = 103 | issue = 5 | pages = 627–641 | year = 1996 | pmid = 8811507 | doi = 10.1007/bf01273159| s2cid = 33701841 }} It has also been investigated as a therapy for Parkinson's disease and prolactinoma.{{cite journal |vauthors=Bravi D, Davis TL, Mouradian MM, Chase TN | title = Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980 | journal = Movement Disorders | volume = 8 | issue = 2 | pages = 195–197 |date=April 1993 | pmid = 8097280 | doi = 10.1002/mds.870080214 | s2cid = 23676084 }}{{cite journal |vauthors=Jaspers C, Benker G, Reinwein D | title = Treatment of prolactinoma patients with the new non-ergot dopamine agonist roxindol: first results | journal = The Clinical Investigator | volume = 72 | issue = 6 | pages = 451–456 |date=June 1994 | pmid = 7950157 | doi = 10.1007/bf00180520| s2cid = 532184 }} However, it has never been marketed.{{cite book | last=Elks | first=J. | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1083 | access-date=2 February 2025 | page=1083}}

Roxindole acts as an agonist at the following receptors:{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Audinot V, Millan MJ | title = Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 359 | issue = 6 | pages = 447–453 | date = June 1999 | pmid = 10431754 | doi = 10.1007/pl00005374 | s2cid = 19721911 | url = http://link.springer.de/link/service/journals/00210/bibs/9359006/93590447.htm | archive-url = https://archive.today/20130211234215/http://link.springer.de/link/service/journals/00210/bibs/9359006/93590447.htm | url-status = dead | archive-date = 2013-02-11 | url-access = subscription }}{{cite journal |vauthors=Heinrich T, Böttcher H, Bartoszyk GD, Greiner HE, Seyfried CA, Van Amsterdam C | title = Indolebutylamines as selective 5-HT(1A) agonists | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 19 | pages = 4677–4683 |date=September 2004 | pmid = 15341483 | doi = 10.1021/jm040792y }}

• D₂ receptor (K_i = 2.82{{nbsp}}nM)
• D₃ receptor (K_i = 1.17{{nbsp}}nM)
• D₄ receptor (K_i = 5.89{{nbsp}}nM)
• 5-HT_1A receptor (K_i = 0.380{{nbsp}}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.{{cite journal | vauthors = Seyfried CA, Greiner HE, Haase AF | title = Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems | journal = European Journal of Pharmacology | volume = 160 | issue = 1 | pages = 31–41 | date = January 1989 | pmid = 2565817 | doi = 10.1016/0014-2999(89)90651-1 }}{{cite journal | vauthors = Bartoszyk GD, Harting J, Minck KO | title = Roxindole: psychopharmacological profile of a dopamine D2 autoreceptor agonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 276 | issue = 1 | pages = 41–48 | date = January 1996 | pmid = 8558454 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8558454 }} Weaker activity at the serotonin 1_B and 1_D receptors has been seen.{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Audinot V, Millan MJ | title = Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 359 | issue = 6 | pages = 447–453 | date = June 1999 | pmid = 10431754 | doi = 10.1007/pl00005374 | s2cid = 19721911 }} 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.{{cite journal | vauthors = Maj J, Kołodziejczyk K, Rogóz Z, Skuza G | title = Roxindole, a dopamine autoreceptor agonist with a potential antidepressant activity. II. Effects on the 5-hydroxytryptamine system | journal = Pharmacopsychiatry | volume = 30 | issue = 2 | pages = 55–61 | date = March 1997 | pmid = 9131725 | doi = 10.1055/s-2007-979483 }}