Molindone

Molindone

Clinical data
Pronunciation	/moʊˈlɪndoʊn/ moh-LIN-dohn
Trade names	Moban
Other names	EN-1733 A; EN1773-A; EN1773A
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a682238
Pregnancy category	C
Routes of administration	By mouth (tablets)[1]
Drug class	Typical antipsychotic
ATC code	N05AE02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	2 hours[2]
Duration of action	24–36 hours[1]
Excretion	Minor, renal and fecal[1]
Identifiers
IUPAC name 3-Ethyl-2-methyl-5-(morpholin-4-ylmethyl)- 1,5,6,7-tetrahydro-4H-indol-4-one
CAS Number	7416-34-4^Y
PubChem CID	23897
IUPHAR/BPS	207
DrugBank	DB01618^N
ChemSpider	22342^Y
UNII	RT3Y3QMF8N
KEGG	D08226^Y
ChEMBL	ChEMBL460^Y
CompTox Dashboard (EPA)	DTXSID9023332
ECHA InfoCard	100.254.109
Chemical and physical data
Formula	C16H24N2O2
Molar mass	276.380 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C2c1c(c([nH]c1CCC2CN3CCOCC3)C)CC
InChI InChI=1S/C16H24N2O2/c1-3-13-11(2)17-14-5-4-12(16(19)15(13)14)10-18-6-8-20-9-7-18/h12,17H,3-10H2,1-2H3^Y Key:KLPWJLBORRMFGK-UHFFFAOYSA-N^Y
^NY (what is this?)  (verify)

Molindone, sold under the brand name Moban, is an antipsychotic medication which is used in the United States in the treatment of schizophrenia.^[2][1][3][4] It is taken by mouth.^[1][2]

Side effects of molindone include extrapyramidal symptoms and tardive dyskinesia, among others.^[2][1] Molindone is thought to work by blocking the effects of dopamine in the brain, leading to diminished symptoms of psychosis.^[2] The drug is sometimes described as a typical antipsychotic,^[5] and sometimes described as an atypical antipsychotic.^[6] Chemically, molindone is an indole and is structurally distinct from many other antipsychotics.^[2]

Molindone was first described by 1966^[7] and was introduced for medical use in 1974.^[8] It remains marketed only in the United States.^[9] The drug has been repurposed and is being developed for potential treatment of aggression in children and adolescents with attention deficit hyperactivity disorder (ADHD).^[10][11][12]

Medical uses

Molindone is used in the treatment of schizophrenia.^[2][1]

Available forms

Molindone is available in the form of 5, 10, 25, and 50 mg oral tablets.^[1]

Adverse effects

Main article: Typical antipsychotic

The side effect profile of molindone is similar to that of other typical antipsychotics. This includes extrapyramidal symptoms and tardive dyskinesia.^[2][1] Unlike most antipsychotics, however, molindone use is associated with decreased appetite and weight loss rather than with weight gain.^[6][13] Molindone may have less potential for sedation than certain other antipsychotics owing to its lack of antihistamine activity.^[2] It has little or no anticholinergic activity and may be less likely than certain other antipsychotics to cause orthostatic hypotension.^[2]

Pharmacology

Pharmacodynamics

Molindone is known to act as a potent antagonist of the dopamine D₂ receptor (IC₅₀Tooltip half-maximal inhibitory concentration = 84–140 nM) and of the serotonin 5-HT_2B receptor (IC₅₀ = 410 nM).^[10][14] It is far less potent as an antagonist of the dopamine D₁, D₃, and D₅ receptors (IC₅₀ = 3,200–8,300 nM) and of the serotonin 5-HT_2A receptor (IC₅₀ = 14,000 nM).^[14] The drug does not significantly bind to or inhibit the α-adrenergic receptors, nor does it affect various other receptors, such as the serotonin 5-HT_1A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors.^[14][2] Likewise, molindone has essentially no affinity for the muscarinic acetylcholine receptors and has very little affinity for the histamine H₁ receptor or the α₁-adrenergic receptor.^[2] However, it has been found to have intermediate affinity for the α₂-adrenergic receptor.^[2] The metabolites of molindone appear to be largely inactive in vitro.^[14] The preceding findings suggest that molindone is pharmacologically distinct from most atypical antipsychotics, which act as potent antagonists of both the D₂ and 5-HT_2A receptors.^[14]

Additional binding data on molindone are also available and in some cases have found contrasting results relative to the above findings, for instance high affinity for the dopamine D₃ receptor.^[15][16]

Molindone is described as an antipsychotic, sedative, and major tranquilizer.^[7] In animals, it reduces spontaneous locomotor activity, inhibits conditioned avoidance responses, produces catalepsy and hypothermia, and limits aggression in monkeys.^[2][1] Like other antipsychotics, molindone antagonizes the effects of the dopamine releasing agent amphetamine and the dopamine receptor agonist apomorphine.^[2][1] In contrast to many antipsychotics however, molindone shows antidepressant-like effects in animals, for example reversing ptosis induced by the dopamine depleting agent tetrabenazine, potentiating 5-hydroxytryptophan (5-HTP)-induced tremors, and potentiating certain effects of levodopa (L-DOPA).^[2][1] It shows little anticholinergic activity in animals and its lack of histamine H₁ receptor antagonism suggests less potential for sedation and weight gain than certain other antipsychotics.^[2] The drug shows antiemetic effects in animals.^[1]

Molindone has been reported to inhibit monoamine oxidase both in vitro and in vivo.^[2] However, very high concentrations (~100,000 nM) and high doses (10 and 40 mg/kg) are required for monoamine oxidase inhibition.^[2] Its inhibition of monoamine oxidase is irreversible and is selective for monoamine oxidase A (MAO-A).^[2] The drug is much more potent in inhibiting monoamine oxidase in vivo than in vitro, suggesting that an active metabolite may be responsible for its monoamine oxidase inhibition.^[2] The MAO-A inhibition of molindone may be responsible for its antidepressant-like effects in animals.^[2] It is unclear whether the monoamine oxidase inhibition of molindone observed in preclinical research occurs therapeutically in humans or is clinically significant.^[2]

It has no affinity for the muscariniac acetylcholine receptors.^[17]

Pharmacokinetics

The elimination half-life of molindone is approximately 2 hours.^[2] This half-life is much shorter than that of most other antipsychotics.^[2] Concentrations of molindone are negligible 12 hours following the last dose even it is used at high doses.^[2] Lithium has been found to prolong the half-life of molindone by at least 4-fold.^[2] In spite of the preceding findings, the duration of action of molindone is 24 to 36 hours.^[2][1] It has been suggested that the antipsychotic effects of molindone may be mediated by active metabolites rather than by molindone itself.^[2]

Chemistry

Molindone is an indole derivative or dihydroindole and is structurally distinct from many other antipsychotics.^[2][1]

Analogues

Some structurally related compounds include L-741,626, losindole, and piquindone. Other indole-containing antipsychotics include ciclindole, flucindole, roxindole, sertindole, and tepirindole.

Synthesis

Patent:^[18][19] Newer patent:^[20]

Condensation of oximinoketone 2 (from nitrosation of 3-pentanone), with cyclohexane-1,3-dione (1) in the presence of zinc and acetic acid leads directly to the partly reduced indole derivative 6. The transformation may be rationalized by assuming as the first step, reduction of 2 to the corresponding α-aminoketone. Conjugate addition of the amine to 1 followed by elimination of hydroxide (as water) would give ene-aminoketone 3. This enamine may be assumed to be in tautomeric equilibrium with imine 4. Aldol condensation of the side chain carbonyl group with the doubly activated ring methylene group would then result in cyclization to pyrrole 5; simple tautomeric transformation would then give the observed product. Mannich reaction of 6 with formaldehyde and morpholine gives the tranquilizer molindone (7).

History

Molindone was first described in the literature by 1966.^[7][21][22] It was first approved for medical use, to treat schizophrenia, in 1974 in the United States.^[8]

Society and culture

Availability

Molindone has been marketed in the United States, Finland, and Hong Kong.^[23] In 2000, it was available only in these three countries.^[23] By 2017, molindone continued to be marketed only in the United States.^[9]

The drug was discontinued by its original supplier, Endo Pharmaceuticals, on January 13, 2010.^[24] After having been produced and subsequently discontinued by Core Pharma in 2015 to 2017, molindone is available again from Epic Pharma effective December 2018.^[25]

Research

Depression and anxiety

Molindone has been studied in the treatment of depression and anxiety.^[2] Some antidepressant and anxiolytic effects have been observed in small and old clinical studies, but findings in terms of effectiveness were mixed.^[2]

Aggression in children and adolescents

Molindone was found to reduce aggressive symptoms, including agitation, hostility, and uncooperativeness, in adults with schizophrenia in the 1970s.^[26] Many other antipsychotics have also shown clinical anti-aggressive effects.^[26] Subsequently, molindone was found to potentially be effective in the treatment of hospitalized aggressive children with conduct disorder in a clinical trial comparing it with thioridazine in the 1980s.^[10][11][27] This study eventually led to molindone being developed for treatment of impulsive aggression in youth much later on.^[10]

Low-dose extended-release molindone (developmental code name SPN-810) is under development for the treatment of impulsive aggression in children and adolescents with attention deficit hyperactivity disorder (ADHD).^[12][10] As of May 2024, it is in phase 3 clinical trials for this indication.^[12] Negative effectiveness findings in a phase 3 trial have been reported.^[12] The exact mechanism of action of molindone for this indication is unknown, but has been proposed to be related to dopamine D₂ and serotonin 5-HT_2B receptor antagonism.^[10][14]

References

1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017111s066lbl.pdf
2. Owen RR, Cole JO (August 1989). "Molindone hydrochloride: a review of laboratory and clinical findings". J Clin Psychopharmacol. 9 (4): 268–276. doi:10.1097/00004714-198908000-00006. PMID 2671060.
3. "molindone". F.A. Davis Company.
4. "Molindone".
5. Aparasu RR, Jano E, Johnson ML, Chen H (October 2008). "Hospitalization risk associated with typical and atypical antipsychotic use in community-dwelling elderly patients". Am J Geriatr Pharmacother. 6 (4): 198–204. doi:10.1016/j.amjopharm.2008.10.003. PMID 19028375.
6. Bagnall A, Fenton M, Kleijnen J, Lewis R (2007). Bagnall AM (ed.). "Molindone for schizophrenia and severe mental illness". Cochrane Database Syst Rev (1): CD002083. doi:10.1002/14651858.CD002083.pub2. PMID 17253473.
7. Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 834. ISBN 978-1-4757-2085-3. Retrieved 18 October 2024.
8. National Archives (U.S.) (2013). Federal Register (in German). Office of the Federal Register, National Archives and Records Service, General Services Administration. p. 66742. Retrieved 18 October 2024.
9. "Molindone Uses, Side Effects & Warnings". Archived from the original on 2017-09-27.
10. Robb AS, Schwabe S, Ceresoli-Borroni G, Nasser A, Yu C, Marcus R, Candler SA, Findling RL (March 2019). "A proposed anti-maladaptive aggression agent classification: improving our approach to treating impulsive aggression". Postgrad Med. 131 (2): 129–137. doi:10.1080/00325481.2019.1574401. PMID 30678534.
11. Balia C, Carucci S, Coghill D, Zuddas A (August 2018). "The pharmacological treatment of aggression in children and adolescents with conduct disorder. Do callous-unemotional traits modulate the efficacy of medication?". Neurosci Biobehav Rev. 91: 218–238. doi:10.1016/j.neubiorev.2017.01.024. PMID 28137460.
12. "Molindone - Supernus Pharmaceuticals". AdisInsight. 29 May 2024. Retrieved 18 October 2024.
13. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ (November 1999). "Antipsychotic-induced weight gain: a comprehensive research synthesis". The American Journal of Psychiatry. 156 (11): 1686–1696. doi:10.1176/ajp.156.11.1686. PMID 10553730. S2CID 38635470.
14. Yu C, Gopalakrishnan G (2018). "In vitro pharmacological characterization of SPN-810M (molindone)". J Exp Pharmacol. 10: 65–73. doi:10.2147/JEP.S180777. PMC 6254985. PMID 30538587.
15. Liu T. "BindingDB BDBM50130290 3-Ethyl-2-methyl-5-morpholin-4-ylmethyl-1,5,6,7-tetrahydro-indol-4-one::3-Ethyl-2-methyl-5-morpholin-4-ylmethyl-1,5,6,7-tetrahydro-indol-4-one ( Molindone)::CHEMBL460::MOLINDONE::Moban". BindingDB. Retrieved 18 October 2024.
16. "PDSP Database". UNC (in Zulu). Retrieved 18 October 2024.
17. Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM (January 2023). "A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity". Pharmaceutics. 15 (1): 230. doi:10.3390/pharmaceutics15010230. PMC 9863833. PMID 36678858.
18. SCHOEN KARL, J PACHTER IRWIN; BE 670798  (1965 to Endo Lab).
19. Irwin J Pachter, Karl Schoen, U.S. patent 3,491,093 (1970 to Endo Lab).
20. Martin Hanbauer, et al. WO2014042688 (Supernus Pharmaceuticals Inc).
21. Rubin AA, Yen HC, Pfeffer M (November 1967). "Psychopharmacological profile of molindone". Nature. 216 (5115): 578–579. Bibcode:1967Natur.216..578R. doi:10.1038/216578a0. PMID 4966848.
22. Sugerman AA, Herrmann J (1967). "Molindone: an indole derivative with antipsychotic activity". Clin Pharmacol Ther. 8 (2): 261–265. doi:10.1002/cpt196782261. PMID 6021585.
23. Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 700. ISBN 978-3-88763-075-1. Retrieved 18 October 2024.
24. "Drugs to be Discontinued". www.fda.gov. Archived from the original on 2009-06-03.
25. "NEWS". www.epic-pharma.com. Retrieved 2018-12-12.
26. Itil TM, Wadud A (February 1975). "Treatment of human aggression with major tranquilizers, antidepressants, and newer psychotropic drugs". J Nerv Ment Dis. 160 (2–1): 83–99. doi:10.1097/00005053-197502000-00003. PMID 235010.
27. Greenhill LL, Solomon M, Pleak R, Ambrosini P (August 1985). "Molindone hydrochloride treatment of hospitalized children with conduct disorder". J Clin Psychiatry. 46 (8 Pt 2): 20–25. PMID 3894338.