Details of the Drug Combination

General Information of Drug Combination (ID: DCUGMZJ)

• Drug Combination Name: Pindolol + METHYLENEDIOXYMETHAMPHETAMINE
• Indication: Mood Disorder; Status: Phase 1 [1]
• Component Drugs:
  Pindolol (DMD2NV7): Small molecular drug
  METHYLENEDIOXYMETHAMPHETAMINE (DMYVU47): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pindolol

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]

Pindolol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Antagonist	[4]

Pindolol Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[5]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[6]

Indication(s) of METHYLENEDIOXYMETHAMPHETAMINE

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[3]

METHYLENEDIOXYMETHAMPHETAMINE Interacts with 7 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[7]
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Inhibitor	[7]
5-HT 2B receptor (HTR2B)	TT0K1SC	5HT2B_HUMAN	Agonist	[7]
5-HT 2A receptor (HTR2A)	TTJQOD7	5HT2A_HUMAN	Agonist	[7]
Synaptic vesicle amine transporter (SLC18A2)	TTNZRI3	VMAT2_HUMAN	Antagonist	[7]
Dopamine transporter (DAT)	TTVBI8W	SC6A3_HUMAN	Inhibitor	[7]
5-HT 2C receptor (HTR2C)	TTWJBZ5	5HT2C_HUMAN	Agonist	[7]

METHYLENEDIOXYMETHAMPHETAMINE Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[8]
Cytochrome P450 102A1 (cyp102)	DE4OGUF	CPXB_BACMB	Metabolism	[9]

METHYLENEDIOXYMETHAMPHETAMINE Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[10]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Decreases Activity	[11]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[12]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Lysosome-associated membrane glycoprotein 2 (LAMP2)	OTLUGEJC	LAMP2_HUMAN	Increases Expression	[14]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Activity	[15]
Sodium-dependent noradrenaline transporter (SLC6A2)	OTMHQJMP	SC6A2_HUMAN	Decreases Activity	[16]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Decreases Activity	[16]
Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7)	OTBUSUTE	ACHA7_HUMAN	Increases Activity	[17]
Monocarboxylate transporter 1 (SLC16A1)	OTW1UTZ7	MOT1_HUMAN	Increases Expression	[18]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Expression	[12]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[12]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[12]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[14]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[12]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[12]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[12]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Affects Response To Substance	[19]
Oxytocin receptor (OXTR)	OT7WFW4U	OXYR_HUMAN	Affects Response To Substance	[20]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Acetylation	[21]

References

• [1] ClinicalTrials.gov (NCT00895804) Pharmacological Interaction Between Pindolol and MDMA (3,4-Methylenedioxymethamphetamine)
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 91).
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4574).
• [4] Are we misunderstanding beta-blockers. Int J Cardiol. 2007 Aug 9;120(1):10-27.
• [5] Beta-adrenergic receptor blocking drugs, hypertension and plasma renin. Br J Clin Pharmacol. 1975 Apr;2(2):159-64. doi: 10.1111/j.1365-2125.1975.tb01571.x.
• [6] Effects of chronic pindolol treatment on human myocardial beta 1- and beta 2-adrenoceptor function. Naunyn Schmiedebergs Arch Pharmacol. 1990 Oct;342(4):429-35. doi: 10.1007/BF00169460.
• [7] The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction. 2006 Sep;101(9):1241-5.
• [8] Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit. 2004 Apr;26(2):137-44.
• [9] The bacterial P450 BM3: a prototype for a biocatalyst with human P450 activities. Trends Biotechnol. 2007 Jul;25(7):289-98.
• [10] An in vitro approach to assessing a potential drug interaction between MDMA (ecstasy) and caffeine. Toxicol In Vitro. 2014 Mar;28(2):231-9.
• [11] Inhibition potential of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites on the in vitro monoamine oxidase (MAO)-catalyzed deamination of the neurotransmitters serotonin and dopamine. Toxicol Lett. 2016 Jan 22;243:48-55.
• [12] An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol. 2013 Dec;87(12):2165-85. doi: 10.1007/s00204-013-1082-9. Epub 2013 Jul 3.
• [13] P-glycoprotein modulation by the designer drugs methylenedioxymethamphetamine, methylenedioxyethylamphetamine and paramethoxyamphetamine. Addict Biol. 2003 Dec;8(4):413-8. doi: 10.1080/13556210310001646475.
• [14] Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells. Chem Res Toxicol. 2020 Apr 20;33(4):903-914. doi: 10.1021/acs.chemrestox.9b00437. Epub 2020 Mar 27.
• [15] Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4. Eur Heart J. 2010 Jul;31(14):1780-91. doi: 10.1093/eurheartj/ehp598. Epub 2010 Jan 29.
• [16] Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR. Neurotoxicology. 2019 May;72:95-100. doi: 10.1016/j.neuro.2019.02.011. Epub 2019 Feb 15.
• [17] The effects of 3,4-methylenedioxymethamphetamine (MDMA) on nicotinic receptors: intracellular calcium increase, calpain/caspase 3 activation, and functional upregulation. Toxicol Appl Pharmacol. 2010 May 1;244(3):344-53. doi: 10.1016/j.taap.2010.01.014. Epub 2010 Feb 2.
• [18] Modulation of butyrate transport in Caco-2 cells. Naunyn Schmiedebergs Arch Pharmacol. 2009 Apr;379(4):325-36. doi: 10.1007/s00210-008-0372-x. Epub 2008 Nov 21.
• [19] Involvement of free radicals in MDMA-induced neurotoxicity in mice. Ann Med Interne (Paris). 2001 Apr;152 Suppl 3:IS57-9.
• [20] Oxytocin receptor gene variations and socio-emotional effects of MDMA: A pooled analysis of controlled studies in healthy subjects. PLoS One. 2018 Jun 18;13(6):e0199384. doi: 10.1371/journal.pone.0199384. eCollection 2018.
• [21] N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances. Arch Toxicol. 2023 Jan;97(1):189-199. doi: 10.1007/s00204-022-03383-2. Epub 2022 Sep 23.