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
Eliminationhalf-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
PubChemCID	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 nameMoban, is anantipsychoticmedication which is used in theUnited States in the treatment ofschizophrenia.^[2][1][3][4] It is takenby mouth.^[1][2]

Side effects of molindone includeextrapyramidal symptoms andtardive dyskinesia, among others.^[2][1] Molindone is thought to work byblocking the effects ofdopamine in thebrain, leading to diminished symptoms ofpsychosis.^[2] The drug is sometimes described as atypical antipsychotic,^[5] and sometimes described as anatypical antipsychotic.^[6] Chemically, molindone is anindole 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 theUnited States.^[9] The drug has beenrepurposed and is being developed for potential treatment ofaggression in children and adolescents withattention deficit hyperactivity disorder (ADHD).^[10][11][12]

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

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

The side effect profile of molindone is similar to that of other typical antipsychotics. This includesextrapyramidal symptoms andtardive dyskinesia.^[2][1] Unlike most antipsychotics, however, molindone use is associated withdecreased appetite andweight loss rather than withweight gain.^[6][13] Molindone may have less potential forsedation than certain other antipsychotics owing to its lack ofantihistamine activity.^[2] It has little or noanticholinergic activity and may be less likely than certain other antipsychotics to causeorthostatic hypotension.^[2]

Molindone is known to act as apotentantagonist of thedopamineD₂ receptor (IC₅₀Tooltip half-maximal inhibitory concentration = 84–140 nM) and of theserotonin5-HT_2B receptor (IC₅₀ = 410 nM).[10]^[14] It is far less potent as an antagonist of the dopamineD₁,D₃, andD₅ receptors (IC₅₀ = 3,200–8,300 nM) and of the serotonin5-HT_2A receptor (IC₅₀ = 14,000 nM).[14] The drug does not significantly bind to or inhibit theα-adrenergic receptors, nor does it affect various otherreceptors, such as the serotonin5-HT_1A,5-HT_2C,5-HT₆, and5-HT₇ receptors.^[14][2] Likewise, molindone has essentially noaffinity for themuscarinic acetylcholine receptors and has very little affinity for thehistamineH₁ receptor or theα₁-adrenergic receptor.^[2] However, it has been found to have intermediate affinity for theα₂-adrenergic receptor.^[2] Themetabolites of molindone appear to be largely inactivein vitro.^[14] The preceding findings suggest that molindone ispharmacologically distinct from mostatypical 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 anantipsychotic,sedative, andmajor tranquilizer.^[7] In animals, itreduces spontaneous locomotor activity, inhibitsconditioned avoidance responses, producescatalepsy andhypothermia, and limitsaggression in monkeys.^[2][1] Like other antipsychotics, molindone antagonizes the effects of thedopamine releasing agentamphetamine and thedopamine receptor agonistapomorphine.^[2][1] In contrast to many antipsychotics however, molindone showsantidepressant-like effects in animals, for example reversingptosis induced by thedopamine depleting agenttetrabenazine, potentiating5-hydroxytryptophan (5-HTP)-inducedtremors, and potentiating certain effects oflevodopa (L-DOPA).^[2][1] It shows littleanticholinergic activity in animals and its lack of histamine H₁ receptor antagonism suggests less potential forsedation andweight gain than certain other antipsychotics.^[2] The drug showsantiemetic effects in animals.^[1]

Molindone has been reported toinhibitmonoamine oxidase bothin vitro andin vivo.^[2] However, very high concentrations (~100,000 nM) and high doses (10 and 40 mg/kg) are required formonoamine oxidase inhibition.^[2] Its inhibition of monoamine oxidase isirreversible and isselective formonoamine oxidase A (MAO-A).^[2] The drug is much more potent in inhibiting monoamine oxidasein vivo thanin vitro, suggesting that anactive 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 inpreclinical research occurs therapeutically in humans or is clinically significant.^[2]

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

Theelimination 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, theduration of action of molindone is 24 to 36 hours.^[2][1] It has been suggested that the antipsychotic effects of molindone may be mediated byactive metabolites rather than by molindone itself.^[2]

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

Somestructurally related compounds includeL-741,626,losindole, andpiquindone. Other indole-containing antipsychotics includeciclindole,flucindole,roxindole,sertindole, andtepirindole.

Condensation of oximinoketone2 (fromnitrosation of 3-pentanone), with cyclohexane-1,3-dione (1) in the presence of zinc and acetic acid leads directly to the partly reduced indole derivative6. The transformation may be rationalized by assuming as the first step, reduction of2 to the corresponding α-aminoketone.Conjugate addition of the amine to1 followed by elimination of hydroxide (as water) would give ene-aminoketone3. This enamine may be assumed to be intautomeric equilibrium with imine4.Aldol condensation of the side chain carbonyl group with the doubly activated ringmethylene group would then result in cyclization to pyrrole5; simple tautomeric transformation would then give the observed product.Mannich reaction of6 with formaldehyde and morpholine gives the tranquilizer molindone (7).

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 theUnited States.^[8]

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

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

Molindone was found to reduceaggressive symptoms, includingagitation,hostility, anduncooperativeness, in adults with schizophrenia in the 1970s.^[26] Many other antipsychotics have also shown clinicalanti-aggressive effects.^[26] Subsequently, molindone was found to potentially be effective in the treatment of hospitalized aggressive children withconduct disorder in aclinical trial comparing it withthioridazine in the 1980s.^[10][11][27] This study eventually led to molindone being developed for treatment ofimpulsive aggression in youth much later on.^[10]

Low-doseextended-release molindone (developmental code name SPN-810) is under development for the treatment ofimpulsiveaggression in children and adolescents withattention deficit hyperactivity disorder (ADHD).^[12][10] As of May 2024, it is inphase 3 clinical trials for this indication.^[12] Negative effectiveness findings in a phase 3 trial have been reported.^[12] The exactmechanism of action of molindone for this indication is unknown, but has been proposed to be related todopamineD₂ andserotonin5-HT_2B receptorantagonism.^[10][14]

• 4-Morpholinyl compounds
• 5-HT2B antagonists
• Antiaggressive drugs
• Antipsychotics
• D2 antagonists
• Indoles
• Ketones
• Monoamine oxidase inhibitors

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