DT-Web

DB01618 - Molindone


Identification
Name Molindone
Accession Number DB01618
Type small molecule
Description An indole derivative effective in schizophrenia and other psychoses and possibly useful in the treatment of the aggressive type of undersocialized conduct disorder. Molindone has much lower affinity for D2 receptors than most antipsychotic agents and has a relatively low affinity for D1 receptors. It has only low to moderate affinity for cholinergic and alpha-adrenergic receptors. Some electrophysiologic data from animals indicate that molindone has certain characteristics that resemble those of clozapine. (From AMA Drug Evaluations Annual, 1994, p283)
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 276.374
Groups approved
Monoisotopic Weight 276.183778022
Pharmacology
Indication Molindone is used for the management of the manifestations of psychotic disorders.
Mechanism of action The exact mechanism has not been established, however, based on electroencephalogram (EEG) studies, molindone is thought to act by occupying (antagonizing) dopamine (D2) receptor sites in the reticular limbic systems in the brain, thus decreasing dopamine activity. Decreased dopamine activity results in decreased physiological effects normally induced by excessive dopamine stimulation, such as those typically seen in manifestations of psychotic disorders.
Absorption Rapidly absorbed from the gastrointestinal tract following oral administration.
Protein binding Not Available
Biotransformation Most likely hepatic. 36 metabolites have been recognized, some of which may be active.
Route of elimination Human metabolic studies show molindone to be rapidly absorbed and metabolized when given orally. There are 36 recognized metabolites with less than 2-3% unmetabolized molindone being excreted in urine and feces.
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Donepezil Possible antagonism of action
Galantamine Possible antagonism of action
Tacrine The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Molindone, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.
Tetrabenazine May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.
Trimethobenzamide Trimethobenzamide and Molindone, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Triprolidine Triprolidine and Molindone, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
Trospium Trospium and Molindone, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Food Interactions Not Available

Targets


D(2) dopamine receptor
Name D(2) dopamine receptor
Gene Name DRD2
Pharmacological action yes
Actions antagonist
References
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Seeman P, Tallerico T: Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry. 1998 Mar;3(2):123-34. - Pubmed
  • Lidow MS, Goldman-Rakic PS: Differential regulation of D2 and D4 dopamine receptor mRNAs in the primate cerebral cortex vs. neostriatum: effects of chronic treatment with typical and atypical antipsychotic drugs. J Pharmacol Exp Ther. 1997 Nov;283(2):939-46. - Pubmed
  • Froimowitz M, Cody V: The incorporation of butyrophenones and related compounds into a pharmacophore for dopamine D2 antagonists. Drug Des Discov. 1997 Aug;15(2):63-81. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.362
5-hydroxytryptamine 1A receptor
Name 5-hydroxytryptamine 1A receptor
Gene Name HTR1A
Pharmacological action unknown
Actions antagonist
References
  • Nguyen TV, Juorio AV: Down-regulation of tryptamine binding sites following chronic molindone administration. A comparison with responses of dopamine and 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1989 Oct;340(4):366-71. - Pubmed
DTHybrid score 0.2726
5-hydroxytryptamine 2A receptor
Name 5-hydroxytryptamine 2A receptor
Gene Name HTR2A
Pharmacological action unknown
Actions antagonist
References
  • Nguyen TV, Juorio AV: Down-regulation of tryptamine binding sites following chronic molindone administration. A comparison with responses of dopamine and 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1989 Oct;340(4):366-71. - Pubmed
DTHybrid score 0.3157
Muscarinic acetylcholine receptor M1
Name Muscarinic acetylcholine receptor M1
Gene Name CHRM1
Pharmacological action unknown
Actions other/unknown
References
  • Neeper R, Richelson E, Nelson A: Neuroleptic binding to muscarinic M2 receptors of normal human heart in vitro and comparison with binding to M1 and dopamine D2 receptors of brain. Neuropharmacology. 1991 May;30(5):527-9. - Pubmed
DTHybrid score 0.4287

Predictions


Id Partner name Gene Name Score
23 D(1A) dopamine receptor DRD1 0.1751
4119 Cytochrome P450 2D6 CYP2D6 0.1637
617 Muscarinic acetylcholine receptor M2 CHRM2 0.1601
51 Muscarinic acetylcholine receptor M3 CHRM3 0.1493
590 5-hydroxytryptamine 2C receptor HTR2C 0.1237
556 Alpha-1A adrenergic receptor ADRA1A 0.1211
4512 Cytochrome P450 3A4 CYP3A4 0.1097
638 D(3) dopamine receptor DRD3 0.1075
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0993
318 Alpha-2A adrenergic receptor ADRA2A 0.0948
432 D(4) dopamine receptor DRD4 0.0902
492 Histamine H1 receptor HRH1 0.0901
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0887
885 5-hydroxytryptamine 1B receptor HTR1B 0.084
378 Alpha-2C adrenergic receptor ADRA2C 0.0759
725 5-hydroxytryptamine 1D receptor HTR1D 0.0747
632 Alpha-1B adrenergic receptor ADRA1B 0.0742
436 5-hydroxytryptamine 2B receptor HTR2B 0.0736
629 Alpha-2B adrenergic receptor ADRA2B 0.0732
4200 Cytochrome P450 1A2 CYP1A2 0.0711
716 5-hydroxytryptamine 7 receptor HTR7 0.0706
1588 Multidrug resistance protein 1 ABCB1 0.0686
163 D(1B) dopamine receptor DRD5 0.0673
824 Sodium-dependent serotonin transporter SLC6A4 0.0512
6016 Cytochrome P450 2C19 CYP2C19 0.04
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0395
1256 5-hydroxytryptamine 6 receptor HTR6 0.0395
94 5-hydroxytryptamine 4 receptor HTR4 0.0381
789 Alpha-1D adrenergic receptor ADRA1D 0.0377
4118 Cytochrome P450 3A5 CYP3A5 0.0375
6145 Solute carrier family 22 member 1 SLC22A1 0.0371
4757 Cytochrome P450 2C9 CYP2C9 0.0366
6107 Cytochrome P450 3A7 CYP3A7 0.0317
587 Serum albumin ALB 0.0308
3923 Cholinesterase BCHE 0.0302
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0301
6013 Cytochrome P450 2E1 CYP2E1 0.0288
193 Beta-1 adrenergic receptor ADRB1 0.0285
766 Beta-2 adrenergic receptor ADRB2 0.0279
3941 Amine oxidase [flavin-containing] A MAOA 0.0219
713 Sodium-dependent dopamine transporter SLC6A3 0.0218
511 5-hydroxytryptamine 1F receptor HTR1F 0.0216
6030 Cytochrome P450 2B6 CYP2B6 0.0207
528 5-hydroxytryptamine 1E receptor HTR1E 0.0206
706 Glutamate [NMDA] receptor subunit 3A GRIN3A 0.0204
341 5-hydroxytryptamine 3 receptor HTR3A 0.0201
124 Histamine H2 receptor HRH2 0.0199
174 Sigma 1-type opioid receptor SIGMAR1 0.0194
4924 Cytochrome P450 2C8 CYP2C8 0.0188
750 Voltage-dependent calcium channel gamma-1 subunit CACNG1 0.0175
3876 Aromatic-L-amino-acid decarboxylase DDC 0.016
923 Glutamate receptor 3 GRIA3 0.0149
465 Calmodulin CALM1 0.0139
734 D1 dopamine receptor-interacting protein calcyon CALY 0.0137
131 Synaptic vesicular amine transporter SLC18A2 0.0131
1656 CYP2B protein CYP2B 0.0131
6144 Solute carrier family 22 member 2 SLC22A2 0.0128
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0109
6024 Cytochrome P450 1A1 CYP1A1 0.0108
6106 Cytochrome P450 2C18 CYP2C18 0.0099
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0097
813 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2 0.0094
1517 Beta-3 adrenergic receptor ADRB3 0.0094
921 Glutamate receptor 2 GRIA2 0.0092
5718 Cytochrome P450 2A6 CYP2A6 0.0091
474 Acetylcholinesterase ACHE 0.0088
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0086
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0078
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0078
833 Organic cation/carnitine transporter 1 SLC22A4 0.0077
6023 Cytochrome P450 11B2, mitochondrial CYP11B2 0.0069
380 Cytochrome P450 17A1 CYP17A1 0.0068
118 Organic cation/carnitine transporter 2 SLC22A5 0.0065
3939 Amine oxidase [flavin-containing] B MAOB 0.0061
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0061
6432 Transporter snf 0.006
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0058
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0058
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0057
723 Cytosolic phospholipase A2 PLA2G4A 0.0057
20 Prostaglandin G/H synthase 1 PTGS1 0.0055
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0053
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0052
5878 Alpha-7 nicotinic cholinergic receptor subunit CHRFAM7A 0.0044
2129 Sucrase-isomaltase, intestinal SI 0.0043
3426 Glutamine synthetase glnA 0.0043
3987 Glutamine synthetase GLUL 0.0043
6859 Protein S100-A4 S100A4 0.0041
6100 BDNF/NT-3 growth factors receptor NTRK2 0.004
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.004
694 Matrix protein 2 M 0.0039
776 Bile salt export pump ABCB11 0.0039
696 Kappa-type opioid receptor OPRK1 0.0037
6147 Solute carrier family 22 member 3 SLC22A3 0.0036
164 Histamine H4 receptor HRH4 0.0036
427 Substance-P receptor TACR1 0.0034
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0033
1618 High affinity nerve growth factor receptor NTRK1 0.0031
220 Sodium channel protein type 5 subunit alpha SCN5A 0.003
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.003
1561 Troponin C, slow skeletal and cardiac muscles TNNC1 0.0027
1360 Sphingomyelin phosphodiesterase SMPD1 0.0026
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0025
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0025
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0025
866 Large neutral amino acids transporter small subunit 2 SLC7A8 0.0024
858 Potassium voltage-gated channel subfamily A member 1 KCNA1 0.0024
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0024
4115 Voltage-dependent L-type calcium channel subunit alpha-1D CACNA1D 0.0023
245 Large neutral amino acids transporter small subunit 1 SLC7A5 0.0023
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.0023
847 Mu-type opioid receptor OPRM1 0.0021
1898 Cytochrome P450 1B1 CYP1B1 0.0021
215 Sodium channel protein type 11 subunit alpha SCN11A 0.0021
3947 Xanthine dehydrogenase/oxidase XDH 0.002
467 Delta-type opioid receptor OPRD1 0.0019
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0018
4113 Voltage-dependent L-type calcium channel subunit alpha-1F CACNA1F 0.0018
15 Voltage-dependent T-type calcium channel subunit alpha-1I CACNA1I 0.0018
535 Voltage-dependent T-type calcium channel subunit alpha-1G CACNA1G 0.0017
6151 Monocarboxylate transporter 10 SLC16A10 0.0016
904 Glutathione S-transferase P GSTP1 0.0016
964 Voltage-dependent T-type calcium channel subunit alpha-1H CACNA1H 0.0016
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0015
4111 Voltage-dependent L-type calcium channel subunit alpha-1S CACNA1S 0.0015
153 Dopamine beta-hydroxylase DBH 0.0014
198 Sodium channel protein type 10 subunit alpha SCN10A 0.0014
6047 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A PDE1A 0.0012
3810 Catechol O-methyltransferase COMT 0.0012
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0011
762 Voltage-dependent calcium channel subunit alpha-2/delta-1 CACNA2D1 0.0009
4110 Voltage-dependent L-type calcium channel subunit beta-2 CACNB2 0.0009
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