Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4H1MQ)

• DTT Name: Neuronal acetylcholine receptor alpha-4 (CHRNA4)
• Synonyms: Nicotinic acetylcholine receptor alpha4; CHRNA4; Alpha-4 nAChR
• Gene Name: CHRNA4
• DTT Type: Successful target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: ACHA4_HUMAN
• TTD ID: T70967
• Sequence:
  MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
  VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR
  PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG
  SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR
  RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS
  LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR
  PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP
  SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG
  GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV
  SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR
  IFLWMFIIVCLLGTVGLFLPPWLAGMI
• Function: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasmamembrane permeable to sodium ions.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic synapse (hsa04725)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly sodium permeable acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pentolinium	DM38VYQ	Hypotension	BA20-BA21	Approved	[2]
Trimethaphan	DMHF4IQ	Aneurysm	BD51.Z	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CYTISINE	DMUF0BJ	Tobacco dependence	6C4A.2	Phase 3	[3]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-418	DMNP72I	Alzheimer disease	8A20	Discontinued in Phase 2	[4]
ABT-594	DMGMBCW	N. A.	N. A.	Discontinued in Phase 2	[5]
HOMOEPIBATIDINE	DMHP9WV	N. A.	N. A.	Terminated	[3]

16 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol	DMDUI8R	Discovery agent	N.A.	Investigative	[6]
(2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol	DMDUGZS	Discovery agent	N.A.	Investigative	[6]
3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine	DMJB1KL	Discovery agent	N.A.	Investigative	[7]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[8]
6'-methylepibatidine	DMTG8D0	Discovery agent	N.A.	Investigative	[9]
Barbituric acid derivative	DM2I19P	Discovery agent	N.A.	Investigative	[10]
BOLDINE	DMMVB5P	Discovery agent	N.A.	Investigative	[11]
CMI-489	DM4PWDJ	Discovery agent	N.A.	Investigative	[9]
N,N-dimethyl(pyridin-3-yl)methanamine	DM41C8E	Discovery agent	N.A.	Investigative	[12]
N,N-dimethyl-2-(pyridin-3-yloxy)ethanamine	DMMD9A0	Discovery agent	N.A.	Investigative	[12]
N,N-dimethyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMLX0PI	Discovery agent	N.A.	Investigative	[12]
N-ethyl-N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMMKSGL	Discovery agent	N.A.	Investigative	[12]
N-methyl-2-(pyridin-3-yloxy)ethanamine	DMXS43P	Discovery agent	N.A.	Investigative	[12]
N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMMNIRC	Discovery agent	N.A.	Investigative	[12]
N-methyl-N-(pyridin-3-ylmethyl)ethanamine	DMOP128	Discovery agent	N.A.	Investigative	[12]
Predicentrine methiodide	DM2HN4D	Discovery agent	N.A.	Investigative	[11]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	3.51E-10	-0.15	-0.61
Irritable bowel syndrome	DD91.0	Rectal colon tissue	1.09E-01	-3.94E-03	-0.02
Schizophrenia	6A20	Pre-frontal cortex	7.65E-01	0.02	0.15
Schizophrenia	6A20	Superior temporal cortex	9.89E-01	-0.01	-0.11

References

• [1] Mechanism of long-lasting block of ganglion nicotinic receptors by mono-ammonium compounds with long aliphatic chain. J Auton Nerv Syst. 1994 Aug;48(3):231-40.
• [2] Nicotinic and nonnicotinic receptor-mediated actions of vinblastine. Proc Soc Exp Biol Med. 1993 Jul;203(3):372-6.
• [3] Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.
• [4] (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther. 1994 Jul;270(1):319-28.
• [5] The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions. Neuroreport. 1999 Dec 16;10(18):3909-13.
• [6] Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48.
• [7] Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4283-6.
• [8] 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.
• [9] Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine. J Med Chem. 2007 Dec 13;50(25):6383-91.
• [10] Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
• [11] Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72.
• [12] Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594. Bioorg Med Chem Lett. 2006 Apr 1;16(7):2013-6.