Details of the Drug

General Information of Drug (ID: DMWHEV8)

• Drug Name: [3H]spiperone
• Synonyms: Spiperone; spiperone; Spiroperidol; Spiropitan; 749-02-0; Espiperona; Spiperonum; [3H]-spiperone; R 5147; Spiperonum [INN-Latin]; Espiperona [INN-Spanish]; E 525; UNII-4X6E73CJ0Q; NSC 170983; MLS000028615; Spiperone [USAN:INN:BAN:JAN]; 8-(3-(p-Fluorobenzoyl)propyl)-1-phenyl-1,3,8-triazaspiro(45)decan-4-one; 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[45]decan-4-one; 8-(3-p-Fluorobenzoyl-1-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro(4,5)decane; EINECS 212-024-0; BRN 0632204; SMR000058674; [3H]-spiperone; SPIPERONE

Indication

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[1], [2]

• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 395.5
  Topological Polar Surface Area (xlogp); 3
  Rotatable Bond Count (rotbonds); 6
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 5
• Chemical Identifiers:
  Formula: C23H26FN3O2
  IUPAC Name: 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
  Canonical SMILES: C1CN(CCC12C(=O)NCN2C3=CC=CC=C3)CCCC(=O)C4=CC=C(C=C4)F
  InChI: InChI=1S/C23H26FN3O2/c24-19-10-8-18(9-11-19)21(28)7-4-14-26-15-12-23(13-16-26)22(29)25-17-27(23)20-5-2-1-3-6-20/h1-3,5-6,8-11H,4,7,12-17H2,(H,25,29)
  InChIKey: DKGZKTPJOSAWFA-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 5265
  ChEBI ID: CHEBI:9233
  CAS Number: 749-02-0
  TTD ID: D05EQG
  VARIDT ID: DR01493

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
5-HT 1A receptor (HTR1A)	TTSQIFT	5HT1A_HUMAN	Inhibitor	[3]
5-HT 2A receptor (HTR2A)	TTJQOD7	5HT2A_HUMAN	Inhibitor	[4]
5-HT 6 receptor (HTR6)	TTJS8PY	5HT6R_HUMAN	Inhibitor	[5]
5-HT 7 receptor (HTR7)	TTO9X1H	5HT7R_HUMAN	Inhibitor	[5]
Adrenergic receptor alpha-1A (ADRA1A)	TTNGILX	ADA1A_HUMAN	Inhibitor	[6]
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Antagonist	[7], [8]
Dopamine D3 receptor (D3R)	TT4C8EA	DRD3_HUMAN	Antagonist	[7], [9]
Dopamine D4 receptor (D4R)	TTE0A2F	DRD4_HUMAN	Antagonist	[10], [9]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[11]

Molecular Expression Atlas of This Drug

• The Studied Disease: Discovery agent
• ICD Disease Classification: N.A.

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
5-HT 1A receptor (HTR1A)	DTT	HTR1A	1.49E-05	-0.22	-0.58
5-HT 6 receptor (HTR6)	DTT	HTR6	1.23E-05	-0.12	-0.71
Dopamine D2 receptor (D2R)	DTT	DRD2	2.50E-02	-0.08	-0.49
P-glycoprotein 1 (ABCB1)	DTP	P-GP	9.39E-02	1.07E-01	2.80E-01

References

• [1] 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: 3300).
• [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: 99).
• [3] Synthesis of (R,S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetral in (trans-8-OH-PIPAT): a new 5-HT1A receptor ligand. J Med Chem. 1993 Oct 15;36(21):3161-5.
• [4] Activity of Parthenolide at 5HT2A receptors. J Nat Prod. 1997 Jun;60(6):651-3.
• [5] Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7). J Med Chem. 2003 Jul 3;46(14):2795-812.
• [6] Pharmacophore identification of alpha(1A)-adrenoceptor antagonists. Bioorg Med Chem Lett. 2005 Feb 1;15(3):657-64.
• [7] Regulation of human D(1), d(2(long)), d(2(short)), D(3) and D(4) dopamine receptors by amiloride and amiloride analogues. Br J Pharmacol. 2000 Jul;130(5):1045-59.
• [8] Synthesis and structure-activity relationships of 1-aralkyl-4-benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent sigma ligands. J Med Chem. 2005 Jan 13;48(1):266-73.
• [9] Modeling the similarity and divergence of dopamine D2-like receptors and identification of validated ligand-receptor complexes. J Med Chem. 2005 Feb 10;48(3):694-709.
• [10] Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci Lett. 1995 Feb 17;186(2-3):145-8.
• [11] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [12] MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents. Cancer Chemother Pharmacol. 2009 Jun;64(1):183-8.
• [13] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [14] Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. Pregnancy Hypertens. 2012 Apr;2(2):123-31.
• [15] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [16] Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92.
• [17] Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit. 2011 Apr;33(2):244-50.
• [18] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [19] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [20] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031127)
• [21] Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease. Clin Neuropharmacol. 1998 May-Jun;21(3):141-51.
• [22] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [23] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [24] Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D 2 /D 3 Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants. Clin Pharmacol Drug Dev. 2021 Jan 18.
• [25] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [26] Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010 Sep;13(8):1021-33.
• [27] 5-HT6 receptors and Alzheimer's disease. Alzheimers Res Ther. 2013; 5(2): 15.
• [28] Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea. Curr Opin Investig Drugs. 2010 January; 11(1): 80-91.
• [29] Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat Rev Drug Discov. 2018 Nov;17(11):804-822.
• [30] The Serotonin-6 Receptor as a Novel Therapeutic Target. Exp Neurobiol. 2011 December; 20(4): 159-168.
• [31] PF-05212377 Alzheimer's Disease (Phase 2). Pfizer.
• [32] Activation of 5-HT6 receptors modulates sleep-wake activity and hippocampal theta oscillation. ACS Chem Neurosci. 2013 Jan 16;4(1):191-9.
• [33] Novel and Potent 5-Piperazinyl Methyl-N1-aryl Sulfonyl Indole Derivatives as 5-HT6 Receptor Ligands. ACS Med Chem Lett. 2010 October 14; 1(7): 340-344.
• [34] Dopamine/serotonin receptor ligands. 9. Oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 ... J Med Chem. 2004 Aug 12;47(17):4155-8.
• [35] Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI. Psychopharmacology (Berl). 2009 Apr;203(2):265-77.
• [36] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [37] Activation of dopamine D4 receptors by ABT-724 induces penile erection in rats. Proc Natl Acad Sci U S A. 2004 April 27; 101(17): 6758-6763.
• [38] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014237)
• [39] I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. J Pharmacol Exp Ther. 1997 Aug;282(2):1011-9.
• [40] Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol. 2004 Aug;370(2):114-23.
• [41] Current and novel approaches to the drug treatment of schizophrenia. J Med Chem. 2001 Feb 15;44(4):477-501.
• [42] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [43] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [44] Anxiolytic effects of aniracetam in three different mouse models of anxiety and the underlying mechanism. Eur J Pharmacol. 2001 May 18;420(1):33-43.
• [45] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [46] Beneficial effects of sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, supplemented with pioglitazone on diabetic model mice. Endocr Res. 2009;34(1-2):18-30.
• [47] Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day.Schizophr Res.2012 Nov;141(2-3):144-52.
• [48] Clinical pipeline report, company report or official report of Lundbeck.
• [49] The Detection of Dopamine Gene Receptors (DRD1-DRD5) Expression on Human Peripheral Blood Lymphocytes by Real Time PCR. Iran J Allergy Asthma Immunol. 2004 Dec;3(4):169-74.
• [50] Dopaminergic synapses in the matrix of the ventrolateral striatum after chronic haloperidol treatment. Synapse. 2002 Aug;45(2):78-85.
• [51] CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics. 2007 Nov;17(11):989-93.
• [52] Synthesis and in vitro binding of N-phenyl piperazine analogs as potential dopamine D3 receptor ligands. Bioorg Med Chem. 2005 Jan 3;13(1):77-87.
• [53] Screening of domperidone in wastewater by high performance liquid chromatography and solid phase extraction methods. Talanta. 2006 Jan 15;68(3):928-31.
• [54] 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: 3639).
• [55] Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors. Eur J Pharmacol. 2009 Apr 1;607(1-3):35-40.
• [56] [The benzamides tiapride, sulpiride, and amisulpride in treatment for Tourette's syndrome]. Nervenarzt. 2007 Mar;78(3):264, 266-8, 270-1.
• [57] Modulatory role of dopamine D2 receptors and fundamental role of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral... Eur J Pharmacol. 2009 Mar 15;606(1-3):90-3.
• [58] Interactions between corticotropin-releasing hormone and serotonin: implications for the aetiology and treatment of anxiety disorders. Handb Exp Pharmacol. 2005;(169):181-204.
• [59] Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors.Pharmacol Biochem Behav.2014 Sep;124:245-9.
• [60] 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
• [61] Synthesis of new derivatives of 8-OH-DPAT: Influence of substitution on the aromatic ring on the pharmacological profile, Bioorg. Med. Chem. Lett. 3(10):2035-2038 (1993).
• [62] Urapidil. A reappraisal of its use in the management of hypertension. Drugs. 1998 Nov;56(5):929-55.
• [63] Clinical pipeline report, company report or official report of Jazz Pharmaceuticals.
• [64] Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity. Front Behav Neurosci. 2015 Jan 15;8:453.
• [65] AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders. J Alzheimers Dis. 2016 May 25;53(2):583-620.
• [66] Pharmacological characteristics of ATI-9242, a Novel Atypical Antipsychotic. FASEB J, April, 2010, 24(Meeting Abstract Supplement),773.12.
• [67] 5-HT1A receptor ligands and their therapeutic applications: review of new patents.Expert Opin Ther Pat. 2018 Sep;28(9):679-689.
• [68] Acyltransferase inhibitors: a patent review (2010-present).Expert Opin Ther Pat. 2015 Feb;25(2):145-58.
• [69] [(3)H]-SB-269970--A selective antagonist radioligand for 5-HT(7) receptors. Br J Pharmacol. 2000 May;130(2):409-17.
• [70] Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [71] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [72] Alpha-Adrenergic activity and cardiovascular effects of besipirdine HCl (HP 749) and metabolite P7480 in vitro and in the conscious rat and dog. J Pharmacol Exp Ther. 1997 Apr;281(1):337-46.
• [73] A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic recep... J Med Chem. 1994 Jul 22;37(15):2328-33.
• [74] 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. J Med Chem. 1996 Jan 5;39(1):143-8.