Molindone primarily targets dopamine D2 receptors in the brain, particularly in the reticular activating and limbic systems, thereby decreasing dopamine excess in these regions. It selectively inhibits radioligand binding to dopamine D2 receptors in rat brain homogenates with an IC50 of 56 nM, while its affinity for D1 receptors is significantly lower (IC50 > 10,000 nM). However, in vivo, Molindone inhibits radioligand binding to both D2 and D1 receptors with ED50 values of 4.9 and 51 mg/kg, respectively. In addition to D2 receptors, Molindone exhibits antagonistic activity at D2S, D2L, and D5 dopamine receptors, as well as 5-HT2B serotonin receptors. It also inhibits type A monoamine oxidase (MAO-A). Compared to tryptamine or 5-HT receptors, Molindone binds more selectively to dopamine receptors. Its ability to inhibit MAO-A leads to increased levels of tryptamine, which may contribute to its antidepressant-like effects.

In vitro studies have demonstrated that Molindone acts as a dopamine receptor antagonist with selectivity for D2 over D1 receptors. Radioligand binding assays in rat brain homogenates have shown that Molindone inhibits binding to D2 receptors with an IC50 of 56 nM, while its IC50 for D1 receptors is greater than 10,000 nM. This selectivity is consistent with its antipsychotic activity, as D2 receptor antagonism is the primary mechanism underlying the therapeutic effects of antipsychotic drugs. In functional assays, Molindone (0.4-0.8 mg/kg) reverses depression of dopamine neurons induced by D-amphetamine and apomorphine and increases dopamine synthesis and dihydroxyphenylacetic acid (DOPAC) levels in the striatum and olfactory tubercles in rats. It suppresses spontaneous locomotion and blocks conditioned avoidance responses in male mice and female rats. Furthermore, Molindone inhibits climbing behavior in mice induced by the D2 receptor agonist bromocriptine. At concentrations of 10^-4 M or greater, Molindone has been found to inhibit the enzyme cardiac adenylate cyclase. It has also been found to decrease tryptamine binding sites.

In vivo, Molindone has been shown to be effective in treating schizophrenia and other psychoses. It exerts its antipsychotic effects by blocking dopamine receptors, probably D2 and D3, in the reticular activating and limbic systems, thereby decreasing dopamine excess in the brain. In animal models, Molindone suppresses spontaneous locomotion and blocks conditioned avoidance responses, which are classic behavioral tests for antipsychotic activity. It also reverses the depression of dopamine neurons induced by psychostimulants and increases dopamine turnover in the striatum. In pigeons, Molindone (0.3-5.6 mg/kg) increases error rates and reduces response rates in learned acquisition tasks. Clinical formulations containing Molindone have been used in the treatment of schizophrenia. The compound's ability to inhibit MAO-A may also contribute to its therapeutic effects, particularly in patients with comorbid depression.

The in vitro receptor binding assays for Molindone involve measuring its affinity for dopamine and serotonin receptors using radioligand binding techniques. Membrane preparations from rat brain homogenates or cells expressing human receptors are incubated with a radiolabeled ligand (e.g., [3H]raclopride for D2, [3H]SCH 23390 for D1) and varying concentrations of Molindone. The bound radioactivity is measured, and the IC50 or Ki values are calculated from competition binding curves. These assays have established that Molindone selectively inhibits D2 receptor binding with an IC50 of 56 nM, while its affinity for D1 receptors is much lower (IC50 > 10,000 nM). In addition, binding assays have demonstrated activity at D5 and 5-HT2B receptors. Functional assays, such as measuring the inhibition of forskolin-stimulated cAMP accumulation, are used to confirm antagonist activity at D2 receptors.

Cellular assays for Molindone are conducted to evaluate its effects on receptor-mediated signaling pathways and cellular function. For dopamine receptor antagonist activity, cells expressing human D2 receptors are treated with Molindone, and the reversal of dopamine-induced inhibition of cAMP production is measured. The compound's ability to inhibit MAO-A can be assessed in cellular systems by measuring the accumulation of monoamine substrates such as tryptamine or serotonin. In rat brain homogenates, Molindone has been shown to inhibit MAO-A activity, leading to increased tryptamine levels. Additionally, Molindone at concentrations of 10^-4 M or greater has been found to inhibit cardiac adenylate cyclase, and it has been shown to decrease tryptamine binding sites. These cellular assays provide functional confirmation of the binding data and help elucidate the compound's mechanism of action.

In vivo animal experiments for Molindone are conducted in rodent models to evaluate its antipsychotic and behavioral effects. The conditioned avoidance response test is a standard model where rats are trained to avoid a foot shock, and the ability of Molindone to suppress avoidance behavior is measured. The amphetamine-induced hyperactivity model assesses the compound's ability to reverse hyperlocomotion induced by psychostimulants. In addition, Molindone's effects on dopamine neuron activity and metabolism have been studied using in vivo microdialysis or tissue sampling techniques. For example, Molindone (0.4-0.8 mg/kg) has been shown to reverse depression of dopamine neurons induced by D-amphetamine and apomorphine and to increase dopamine synthesis and DOPAC levels in the striatum and olfactory tubercles. The compound's effects on learning and behavior have been evaluated in pigeons using repeated acquisition procedures. These in vivo studies provide a comprehensive characterization of Molindone's pharmacological profile.

Molindone hydrochloride has a molecular weight of 312.83 g/mol and a molecular formula of C16H24N2O2·HCl. It is soluble in DMSO at 17.5 mg/mL (55.94 mM). The compound should be stored at -20°C for long-term stability. In vivo, Molindone inhibits radioligand binding to both D2 and D1 receptors with ED50 values of 4.9 and 51 mg/kg, respectively. Its pharmacokinetic profile has been studied in preclinical models, but detailed clinical pharmacokinetic data are limited. The compound's ability to cross the blood-brain barrier is evidenced by its central effects in animal models.

The toxicity profile of Molindone has been evaluated in both preclinical and clinical studies. It is classified as a Dangerous Good for transport. In vitro and in vivo genotoxicity assessments have been conducted to evaluate its safety. Toxicity studies in juvenile and adult rats have also been performed to assess its safety in different age groups. Clinically, Molindone has been associated with side effects such as extrapyramidal symptoms, sedation, and weight gain, although these are generally less severe than with typical antipsychotics. Neuroleptic malignant syndrome, a rare but serious side effect, has been reported with Molindone use. As with all antipsychotics, the risk-benefit ratio must be carefully considered for each patient.

Morinone hydrochloride belongs to the indole class of drugs. Morinone hydrochloride is the hydrochloride salt form of morinone, a dihydroindole ketone compound with antipsychotic and antischizophrenic activity. Its structure is independent of other major sedatives. Morinone hydrochloride works by blocking dopamine receptors (likely D2 and D3 receptors) in the reticular activating system and limbic system, thereby reducing excess levels of dopamine in the brain. This leads to a reduction in spontaneous movement and aggression, inhibition of conditioned reflexes, and antagonism of amphetamine-induced stereotyped behaviors and ADHD. Morinone is an indole derivative effective against schizophrenia and other psychoses and may be used to treat aggressive social disorders. Compared to most antipsychotics, morinone has a much lower affinity for D2 receptors and a relatively lower affinity for D1 receptors. Its affinity for cholinergic and alpha-adrenergic receptors is only low to moderate. Some animal electrophysiological data suggest that morinone possesses certain properties similar to clozapine. (Excerpted from the JAMA Drug Evaluation Yearbook, 1994, p. 283)
See also: Morindone (containing the active ingredient).
Molindone is a dihydroindolone neuroleptic that is structurally distinct from other antipsychotic classes. It has been used clinically for the treatment of schizophrenia and other psychoses. Its mechanism of action involves antagonism at dopamine D2 (including D2S and D2L), D5, and serotonin 5-HT2B receptors, as well as inhibition of MAO-A. The combination of D2 antagonism and MAO-A inhibition is unique among antipsychotics and may contribute to its distinct clinical profile, including potential antidepressant effects. Molindone has been studied in various clinical populations, including hospitalized children with conduct disorder. Despite its efficacy, Molindone is not widely used today, having been largely replaced by newer atypical antipsychotics. Nevertheless, it remains a valuable pharmacological tool for studying dopamine receptor function and the role of MAO-A inhibition in psychiatric disorders.

C16H25CLN2O2

312.83

312.16

15622-65-8

Molindone;7416-34-4;Molindone-d8;1189805-13-7

9883259

Typically exists as solid at room temperature

462.9ºC at 760mmHg

180-181ºC

233.7ºC

9.51E-09mmHg at 25°C

2.702

2

3

3

21

354

0

Cl[H].O1C([H])([H])C([H])([H])N(C([H])([H])C1([H])[H])C([H])([H])C1([H])C(C2C(C([H])([H])C([H])([H])[H])=C(C([H])([H])[H])N([H])C=2C([H])([H])C1([H])[H])=O

GQWNECFJGBQMBO-UHFFFAOYSA-N

InChI=1S/C16H24N2O2.ClH/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;1H

3-ethyl-2-methyl-5-(morpholin-4-ylmethyl)-1,5,6,7-tetrahydroindol-4-one;hydrochloride

Molindone Hydrochloride salt; Molindone Hydrochloride; Molindone HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~319.66 mM)
DMSO : ~17.5 mg/mL (~55.94 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)