Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTE0A2F)

• DTT Name: Dopamine D4 receptor (D4R)
• Synonyms: DRD4; D(2C)D(4) dopamine receptor dopamine receptor
• Gene Name: DRD4
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: DRD4_HUMAN
• TTD ID: T24983
• Sequence:
  MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
  TERALQTPTNSFIVSLAAADLLLALLVLPLFVYSEVQGGAWLLSPRLCDALMAMDVMLCT
  ASIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGR
  DPAVCRLEDRDYVVYSSVCSFFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSG
  PGPPSPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPSLPQDPCGPDCAPPAPG
  LPPDPCGSNCAPPDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWT
  PFFVVHITQALCPACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC
• Function: Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins which inhibit adenylyl cyclase. Modulates the circadian rhythm of contrast sensitivity by regulating the rhythmic expression of NPAS2 in the retinal ganglion cells.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Dopaminergic synapse (hsa04728)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Dopamine receptors (R-HSA-390651)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Clozapine	DMFC71L	Schizophrenia	6A20	Approved	[2]
Phenyltoloxamine	DMKAEQW	Allergy	4A80-4A85	Approved	[1]

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CM-2395	DMASPWR	Schizophrenia	6A20	Phase 3	[3]
L-745,870	DMTGR25	Psychotic disorder	6A20-6A25	Phase 2	[4]
RP5063	DMKUE8O	Schizophrenia	6A20	Phase 2	[5]
NGD 94-1	DMM1Y8F	Schizophrenia	6A20	Phase 1	[6]

8 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-724	DMDQVY4	Erectile dysfunction	HA01.1	Discontinued in Phase 2	[7]
Lu-35138	DMQ7A35	Psychotic disorder	6A20-6A25	Discontinued in Phase 2	[8]
NGD-94-4	DMZ9WLO	Schizophrenia	6A20	Discontinued in Phase 1	[9]
A-80426	DMBC3DG	N. A.	N. A.	Terminated	[10]
Belaperidone	DMM0ZIJ	Schizophrenia	6A20	Terminated	[6]
BIMG80	DM9X1DZ	Psychotic disorder	6A20-6A25	Terminated	[11]
Sonepiprazole	DMFI0GW	Schizophrenia	6A20	Terminated	[6]
YM-43611	DMWI094	Psychotic disorder	6A20-6A25	Terminated	[12]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PD-165167	DMD0GB4	Schizophrenia	6A20	Preclinical	[6]
SPI-376	DMC1WAJ	Schizophrenia	6A20	Preclinical	[6]
U-99363E	DMOIWVC	Schizophrenia	6A20	Preclinical	[6]

60 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-nantenine	DM0L3GE	Discovery agent	N.A.	Investigative	[13]
(4-Ethynyl-cyclohex-3-enyl)-dipropyl-amine	DMHQCRU	Discovery agent	N.A.	Investigative	[14]
(4-Phenylethynyl-cyclohex-3-enyl)-dipropyl-amine	DMQM8O5	Discovery agent	N.A.	Investigative	[14]
1-(4-(1H-pyrazol-1-yl)benzyl)-4-phenylpiperazine	DMUDVRM	Discovery agent	N.A.	Investigative	[15]
1-Benzyl-4-(2-ethynyl-pyrrol-1-yl)-piperidine	DMF0GXD	Discovery agent	N.A.	Investigative	[16]
1-Benzyl-4-(2-iodo-pyrrol-1-yl)-piperidine	DMBRJ5S	Discovery agent	N.A.	Investigative	[16]
1-Benzyl-4-(2-oxazol-5-yl-pyrrol-1-yl)-piperidine	DMSBNY8	Discovery agent	N.A.	Investigative	[16]
1-Benzyl-4-(3-oxazol-5-yl-pyrrol-1-yl)-piperidine	DMCJZVA	Discovery agent	N.A.	Investigative	[16]
1-Benzyl-4-pyrrol-1-yl-piperidine	DMNWEC9	Discovery agent	N.A.	Investigative	[16]
1-Dibenzo[b,f]oxepin-10-yl-4-methyl-piperazine	DMOL2Y0	Discovery agent	N.A.	Investigative	[17]
1-[2-(2-Benzyl-phenoxy)-ethyl]-piperidine	DMTNRG7	Discovery agent	N.A.	Investigative	[1]
1-[2-(2-Benzyl-phenoxy)-ethyl]-pyrrolidine	DMLSU30	Discovery agent	N.A.	Investigative	[1]
1-[3-(2-Benzyl-phenoxy)-propyl]-pyrrolidine	DMD2NXL	Discovery agent	N.A.	Investigative	[1]
3-(2-Benzylamino-ethoxy)-phenol	DMZCTGF	Discovery agent	N.A.	Investigative	[18]
3-(4-Methyl-piperidin-1-ylmethyl)-1H-indole	DM0HYDZ	Discovery agent	N.A.	Investigative	[19]
3-(4-Phenyl-piperazin-1-ylmethyl)-1H-indole	DM17SNR	Discovery agent	N.A.	Investigative	[19]
3-(4-Phenyl-piperidin-1-ylmethyl)-1H-indole	DMM0WGI	Discovery agent	N.A.	Investigative	[19]
4-(2-Benzylamino-ethoxy)-1,3-dihydro-indol-2-one	DMYVD2E	Discovery agent	N.A.	Investigative	[18]
4-(4-Benzyl-piperazin-1-yl)-1H-benzoimidazole	DMXAEW9	Discovery agent	N.A.	Investigative	[20]
4-(4-Benzyl-piperazin-1-yl)-1H-indole	DMWR0AS	Discovery agent	N.A.	Investigative	[20]
4-(4-Benzyl-piperazin-1-yl)-5-chloro-1H-indole	DMZ4237	Discovery agent	N.A.	Investigative	[20]
4-(4-Benzyl-piperazin-1-yl)-7-bromo-1H-indole	DMVAB7U	Discovery agent	N.A.	Investigative	[20]
4-[2-(2-Benzyl-phenoxy)-ethyl]-morpholine	DM08CG7	Discovery agent	N.A.	Investigative	[1]
A-381393	DMI4TVB	Discovery agent	N.A.	Investigative	[4]
A-425444	DMM5XD6	Discovery agent	N.A.	Investigative	[21]
A412997	DMKY9G5	Discovery agent	N.A.	Investigative	[22]
ABT-670	DM6J57N	Discovery agent	N.A.	Investigative	[21]
Benzyl-[2-(1H-indazol-4-yloxy)-ethyl]-amine	DMTC4G0	Discovery agent	N.A.	Investigative	[18]
Benzyl-[2-(1H-indol-4-yloxy)-ethyl]-amine	DMV6DY7	Discovery agent	N.A.	Investigative	[18]
CP-226269	DMGLO2X	Discovery agent	N.A.	Investigative	[23]
E-1455	DMHPFMV	Schizophrenia	6A20	Investigative	[24]
FAUC 113	DMC6J3B	Discovery agent	N.A.	Investigative	[25]
FAUC213	DM1LMFG	Discovery agent	N.A.	Investigative	[23]
FLUMEZAPINE	DMW0HOG	Discovery agent	N.A.	Investigative	[26]
FLUTROLINE	DMUOHVL	Discovery agent	N.A.	Investigative	[27]
ISOCLOZAPINE	DM52CPU	Discovery agent	N.A.	Investigative	[17]
ISOLOXAPINE	DMH1BN4	Discovery agent	N.A.	Investigative	[28]
JL-18	DM0LD3F	Discovery agent	N.A.	Investigative	[29]
L-741626	DMCYQJF	Discovery agent	N.A.	Investigative	[30]
L-741742	DMP75YK	Discovery agent	N.A.	Investigative	[31]
L-750,667	DM2WUKF	Discovery agent	N.A.	Investigative	[32]
ML398	DMA0E2Q	Discovery agent	N.A.	Investigative	[33]
N-(4-Dipropylaminobutyl)-4-biphenylcarboxamide	DMU1ATH	Discovery agent	N.A.	Investigative	[34]
N-(4-Propylaminobutyl)-4-biphenylcarboxamide	DMG9D7A	Discovery agent	N.A.	Investigative	[34]
nafadotride	DM79KLR	Discovery agent	N.A.	Investigative	[32]
PF-592379	DMY93GJ	Discovery agent	N.A.	Investigative	[35]
PG-01037	DM2TP4Q	Discovery agent	N.A.	Investigative	[36]
piribedil	DMNP6QD	Discovery agent	N.A.	Investigative	[37]
QUINPIROLE	DMDNHEP	Discovery agent	N.A.	Investigative	[38]
RBI257	DM9IQXM	Discovery agent	N.A.	Investigative	[23]
Ro 10-4548	DMXT34V	Discovery agent	N.A.	Investigative	[23]
SB-271046	DM5VJAF	Discovery agent	N.A.	Investigative	[39]
STEPHOLIDINE	DMGMXQC	Discovery agent	N.A.	Investigative	[40]
TKP-1002	DMZU4O8	Schizophrenia	6A20	Investigative	[24]
U101958	DM9GOAV	Discovery agent	N.A.	Investigative	[41]
UH-232	DM5K6ZE	Discovery agent	N.A.	Investigative	[42]
[125I]L750667	DMO7VRJ	Discovery agent	N.A.	Investigative	[43]
[2-(1H-Benzoimidazol-4-yloxy)-ethyl]-benzyl-amine	DMSPMHE	Discovery agent	N.A.	Investigative	[18]
[3H]N-methylspiperone	DM5176Y	Discovery agent	N.A.	Investigative	[32]
[3H]spiperone	DMWHEV8	Discovery agent	N.A.	Investigative	[44]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Schizophrenia	6A20	Pre-frontal cortex	1.53E-01	0.03	0.1
Schizophrenia	6A20	Superior temporal cortex	7.13E-01	0.08	0.4
Parkinson's disease	8A00.0	Substantia nigra tissue	1.90E-01	0.19	0.76

References

• [1] 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.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031127)
• [4] 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.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [7] 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.
• [8] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014237)
• [9] 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.
• [10] Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking... J Med Chem. 2005 Mar 24;48(6):2054-71.
• [11] BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. J Neurochem. 1997 Jul;69(1):182-90.
• [12] Effects of YM-43611, a novel dopamine D2-like receptor antagonist, on immediate early gene expression in the rat forebrain. Neuropsychopharmacology. 1997 Jul;17(1):27-33.
• [13] Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.
• [14] Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonis... J Med Chem. 2000 Feb 24;43(4):756-62.
• [15] Synthesis and biological investigations of dopaminergic partial agonists preferentially recognizing the D4 receptor subtype. Bioorg Med Chem Lett. 2006 Jun 1;16(11):2955-9.
• [16] Piperidinylpyrroles: design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands. Bioorg Med Chem Lett. 1999 Nov 1;9(21):3143-6.
• [17] Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain. J Med Chem. 1982 Jul;25(7):855-8.
• [18] New generation dopaminergic agents. 7. Heterocyclic bioisosteres that exploit the 3-OH-phenoxyethylamine D2 template. Bioorg Med Chem Lett. 1999 Sep 6;9(17):2593-8.
• [19] 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4... J Med Chem. 1996 May 10;39(10):1941-2.
• [20] New generation dopaminergic agents. 5. Heterocyclic bioisosteres that exploit the 3-OH-N1-phenylpiperazine dopaminergic template. Bioorg Med Chem Lett. 1998 Oct 6;8(19):2675-80.
• [21] Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzamide (ABT-670), an orally bioavailable dopamine D4 ago... J Med Chem. 2006 Dec 14;49(25):7450-65.
• [22] A-412997 is a selective dopamine D4 receptor agonist in rats. Pharmacol Biochem Behav. 2005 Sep;82(1):140-7.
• [23] Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common recepto... Mol Pharmacol. 2004 Dec;66(6):1491-9.
• [24] 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. (Target id: 217).
• [25] Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine. J Med Chem. 2001 Apr 12;44(8):1151-7.
• [26] Effects of conformationally restricted 4-piperazinyl-10H-thienobenzodiazepine neuroleptics on central dopaminergic and cholinergic systems. J Med Chem. 1982 Oct;25(10):1133-40.
• [27] Neuroleptic activity in 5-aryltetrahydro-gamma-carbolines. J Med Chem. 1980 Jun;23(6):635-43.
• [28] Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain. J Med Chem. 1981 Sep;24(9):1021-6.
• [29] (S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1-yl] benzenesulfonamide, a selective dopamine D4 antagonist. J Med Chem. 1996 Jun 21;39(13):2435-7.
• [30] Synthesis and characterization of selective dopamine D2 receptor antagonists. 2. Azaindole, benzofuran, and benzothiophene analogs of L-741,626. Bioorg Med Chem. 2010 Jul 15;18(14):5291-300.
• [31] 5-(4-Chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxazole: a potent, selective antagonist at human cloned dopamine D4 receptors. J Med Chem. 1996 May 10;39(10):1943-5.
• [32] Nonconserved residues in the second transmembrane-spanning domain of the D(4) dopamine receptor are molecular determinants of D(4)-selective pharmacology. Mol Pharmacol. 2000 Jan;57(1):144-52.
• [33] Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity. ACS Med Chem Lett. 2014 Jul 9;5(9):1060-4.
• [34] Novel D3 selective dopaminergics incorporating enyne units as nonaromatic catechol bioisosteres: synthesis, bioactivity, and mutagenesis studies. J Med Chem. 2008 Nov 13;51(21):6829-38.
• [35] Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats. Behav Pharmacol. 2012 Jun;23(3):280-91.
• [36] Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3... J Med Chem. 2007 Aug 23;50(17):4135-46.
• [37] Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther. 2002 Nov;303(2):791-804.
• [38] Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of he... J Med Chem. 2005 Sep 8;48(18):5771-9.
• [39] Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists. Bioorg Med Chem Lett. 2008 Jan 15;18(2):738-43.
• [40] Dibenzazecine scaffold rebuilding--is the flexibility always essential for high dopamine receptor affinities Bioorg Med Chem. 2009 Oct 1;17(19):6898-907.
• [41] Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor. Eur J Pharmacol. 1997 Mar 19;322(2-3):283-6.
• [42] (Dipropylamino)-tetrahydronaphthofurans: centrally acting serotonin agonists and dopamine agonists-antagonists, Bioorg. Med. Chem. Lett. 7(21):2759-2764 (1997).
• [43] Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor. Mol Pharmacol. 1996 Dec;50(6):1658-64.
• [44] Differential effects of [3H]nemonapride and [3H]spiperone binding on human dopamine D4 receptors. Neurosci Lett. 1995 Feb 17;186(2-3):145-8.