Target Information
| Target General Information | Top | |||||
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| Target ID |
T70967
(Former ID: TTDS00141)
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| Target Name |
Neuronal acetylcholine receptor alpha-4 (CHRNA4)
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| Synonyms |
Nicotinic acetylcholine receptor alpha4; CHRNA4; Alpha-4 nAChR
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| Gene Name |
CHRNA4
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Aneurysm/dissection [ICD-11: BD50] | |||||
| 2 | Hypertensive crisis [ICD-11: BA03] | |||||
| 3 | Hypotension [ICD-11: BA20-BA21] | |||||
| 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.
Click to Show/Hide
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| BioChemical Class |
Neurotransmitter receptor
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| UniProt ID | ||||||
| Sequence |
MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR IFLWMFIIVCLLGTVGLFLPPWLAGMI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T22H7B | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Pentolinium | Drug Info | Approved | Hypotension | [2] | |
| 2 | Trimethaphan | Drug Info | Approved | Aneurysm | [3], [4] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CYTISINE | Drug Info | Phase 3 | Tobacco dependence | [5] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | ABT-418 | Drug Info | Discontinued in Phase 2 | Alzheimer disease | [6] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 3 Antagonist drugs | + | ||||
| 1 | Pentolinium | Drug Info | [7] | |||
| 2 | Trimethaphan | Drug Info | [1] | |||
| 3 | Barbituric acid derivative | Drug Info | [15] | |||
| Inhibitor | [+] 17 Inhibitor drugs | + | ||||
| 1 | CYTISINE | Drug Info | [8] | |||
| 2 | HOMOEPIBATIDINE | Drug Info | [8] | |||
| 3 | (2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol | Drug Info | [11] | |||
| 4 | (2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol | Drug Info | [11] | |||
| 5 | 3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine | Drug Info | [12] | |||
| 6 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [13] | |||
| 7 | 6'-methylepibatidine | Drug Info | [14] | |||
| 8 | BOLDINE | Drug Info | [16] | |||
| 9 | CMI-489 | Drug Info | [14] | |||
| 10 | N,N-dimethyl(pyridin-3-yl)methanamine | Drug Info | [17] | |||
| 11 | N,N-dimethyl-2-(pyridin-3-yloxy)ethanamine | Drug Info | [17] | |||
| 12 | N,N-dimethyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [17] | |||
| 13 | N-ethyl-N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [17] | |||
| 14 | N-methyl-2-(pyridin-3-yloxy)ethanamine | Drug Info | [17] | |||
| 15 | N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [17] | |||
| 16 | N-methyl-N-(pyridin-3-ylmethyl)ethanamine | Drug Info | [17] | |||
| 17 | Predicentrine methiodide | Drug Info | [16] | |||
| Agonist | [+] 2 Agonist drugs | + | ||||
| 1 | ABT-418 | Drug Info | [9] | |||
| 2 | ABT-594 | Drug Info | [10] | |||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Cholinergic synapse | |||||
| 3 | Nicotine addiction | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Nicotinic acetylcholine receptor signaling pathway | |||||
| 2 | Nicotine pharmacodynamics pathway | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Highly sodium permeable acetylcholine nicotinic receptors | |||||
| 2 | Highly calcium permeable postsynaptic nicotinic acetylcholine receptors | |||||
| 3 | Highly calcium permeable nicotinic acetylcholine receptors | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | SIDS Susceptibility Pathways | |||||
| 2 | Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
| 3 | Nicotine Activity on Dopaminergic Neurons | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 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. | |||||
| REF 2 | Drug information of Pentolinium, 2008. eduDrugs. | |||||
| REF 3 | Drug information of Trimethaphan, 2008. eduDrugs. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004036) | |||||
| REF 7 | Nicotinic and nonnicotinic receptor-mediated actions of vinblastine. Proc Soc Exp Biol Med. 1993 Jul;203(3):372-6. | |||||
| REF 8 | Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7. | |||||
| REF 9 | (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 10 | The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions. Neuroreport. 1999 Dec 16;10(18):3909-13. | |||||
| REF 11 | 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. | |||||
| REF 12 | Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4283-6. | |||||
| REF 13 | 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. | |||||
| REF 14 | 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. | |||||
| REF 15 | Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57. | |||||
| REF 16 | Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72. | |||||
| REF 17 | 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. | |||||
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