Target Information

Target General Infomation
Target ID
T70967
Former ID
TTDS00141
Target Name
Neuronal acetylcholine receptor protein, alpha-4 chain
Gene Name
CHRNA4
Synonyms
Alpha-4 nAChR; Nicotinic acetylcholine receptor alpha4; CHRNA4
Target Type
Successful
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Hypertensive emergencies; Aneurysm [ICD9:401-405; ICD10: I10, I72]
Hypotension [ICD9: 458, 796.3; ICD10: I95]
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.
BioChemical Class
Neurotransmitter receptor
Target Validation
T70967
UniProt ID
P43681
Sequence
MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR
PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG
SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR
RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS
LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR
PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP
SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG
GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV
SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR
IFLWMFIIVCLLGTVGLFLPPWLAGMI
Structure
2GVT; 2LLY
Drugs and Mode of Action
Drug(s) Pentolinium Drug Info Approved Hypotension [1]
Trimethaphan Drug Info Approved Hypertensive emergencies; Aneurysm [2], [3]
ABT-418 Drug Info Discontinued in Phase 2 Alzheimer disease [4]
ABT-594 Drug Info Discontinued in Phase 2 Discovery agent [5], [6]
HOMOEPIBATIDINE Drug Info Terminated Discovery agent [7]
Inhibitor (2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol Drug Info [8]
(2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol Drug Info [8]
3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine Drug Info [9]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [10]
6'-methylepibatidine Drug Info [11]
BOLDINE Drug Info [12]
CMI-489 Drug Info [11]
CYTISINE Drug Info [13]
HOMOEPIBATIDINE Drug Info [13]
N,N-dimethyl(pyridin-3-yl)methanamine Drug Info [14]
N,N-dimethyl-2-(pyridin-3-yloxy)ethanamine Drug Info [14]
N,N-dimethyl-4-(pyridin-3-yl)but-3-yn-1-amine Drug Info [14]
N-ethyl-N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine Drug Info [14]
N-methyl-2-(pyridin-3-yloxy)ethanamine Drug Info [14]
N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine Drug Info [14]
N-methyl-N-(pyridin-3-ylmethyl)ethanamine Drug Info [14]
Predicentrine methiodide Drug Info [12]
Agonist ABT-418 Drug Info [15]
ABT-594 Drug Info [16]
Antagonist Barbituric acid derivative Drug Info [17]
Pentolinium Drug Info [18]
Trimethaphan Drug Info [19]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Cholinergic synapse
Nicotine addiction
PANTHER Pathway Nicotinic acetylcholine receptor signaling pathway
Nicotine pharmacodynamics pathway
Reactome Highly sodium permeable acetylcholine nicotinic receptors
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors
Highly calcium permeable nicotinic acetylcholine receptors
WikiPathways SIDS Susceptibility Pathways
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
Nicotine Activity on Dopaminergic Neurons
References
REF 1Drug information of Pentolinium, 2008. eduDrugs.
REF 2Drug information of Trimethaphan, 2008. eduDrugs.
REF 3Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 4Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004036)
REF 5(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: 3989).
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009632)
REF 7Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007531)
REF 8J Med Chem. 2010 Jun 24;53(12):4731-48.Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation.
REF 9Bioorg Med Chem Lett. 2006 Aug 15;16(16):4283-6. Epub 2006 Jun 9.Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors.
REF 10J Med Chem. 2010 Sep 9;53(17):6386-97.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 receptor agonist with unprecedented selectivity and procognitive potential.
REF 11J Med Chem. 2007 Dec 13;50(25):6383-91. Epub 2007 Nov 10.Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine.
REF 12Bioorg Med Chem. 2007 May 15;15(10):3368-72. Epub 2007 Mar 13.Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers.
REF 13Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7. Epub 2006 Aug 28.Epibatidine isomers and analogues: structure-activity relationships.
REF 14Bioorg Med Chem Lett. 2006 Apr 1;16(7):2013-6. Epub 2006 Jan 18.Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594.
REF 15(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.
REF 16The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions. Neuroreport. 1999 Dec 16;10(18):3909-13.
REF 17Whiting PJ: The <span class="caps">GABAA</span> receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
REF 18Nicotinic and nonnicotinic receptor-mediated actions of vinblastine. Proc Soc Exp Biol Med. 1993 Jul;203(3):372-6.
REF 19Mechanism 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.

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