Target Information
| Target General Information | Top | |||||
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| Target ID |
T55815
(Former ID: TTDS00400)
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| Target Name |
Neuronal acetylcholine receptor alpha-2 (CHRNA2)
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| Synonyms |
CHRNA2
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| Gene Name |
CHRNA2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Corneal disease [ICD-11: 9A76-9A78] | |||||
| 2 | Depression [ICD-11: 6A70-6A7Z] | |||||
| 3 | Glaucoma [ICD-11: 9C61] | |||||
| 4 | Nicotine use disorder [ICD-11: 6C4A] | |||||
| 5 | Tonus and reflex abnormality [ICD-11: MB47] | |||||
| 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 plasma membrane.
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| BioChemical Class |
Neurotransmitter receptor
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| UniProt ID | ||||||
| Sequence |
MGPSCPVFLSFTKLSLWWLLLTPAGGEEAKRPPPRAPGDPLSSPSPTALPQGGSHTETED
RLFKHLFRGYNRWARPVPNTSDVVIVRFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKL RWNPTDFGNITSLRVPSEMIWIPDIVLYNNADGEFAVTHMTKAHLFSTGTVHWVPPAIYK SSCSIDVTFFPFDQQNCKMKFGSWTYDKAKIDLEQMEQTVDLKDYWESGEWAIVNATGTY NSKKYDCCAEIYPDVTYAFVIRRLPLFYTINLIIPCLLISCLTVLVFYLPSDCGEKITLC ISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPSTH TMPHWVRGALLGCVPRWLLMNRPPPPVELCHPLRLKLSPSYHWLESNVDAEEREVVVEEE DRWACAGHVAPSVGTLCSHGHLHSGASGPKAEALLQEGELLLSPHMQKALEGVHYIADHL RSEDADSSVKEDWKYVAMVIDRIFLWLFIIVCFLGTIGLFLPPFLAGMI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 8 Approved Drugs | + | ||||
| 1 | Carbachol | Drug Info | Approved | Glaucoma/ocular hypertension | [2], [3] | |
| 2 | Cisatracurium | Drug Info | Approved | Muscle spasm | [4] | |
| 3 | Levallorphan | Drug Info | Approved | Narcotic depression | [5], [6] | |
| 4 | Mivacurium | Drug Info | Approved | Anaesthesia | [4], [7], [8] | |
| 5 | Pipecuronium | Drug Info | Approved | Spasm | [4], [9] | |
| 6 | Rocuronium | Drug Info | Approved | Muscle spasm | [4] | |
| 7 | Tubocurarine | Drug Info | Approved | Anaesthesia | [4], [10], [11] | |
| 8 | Vecuronium | Drug Info | Approved | Spasm | [12], [8] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | CYTISINE | Drug Info | Phase 3 | Tobacco dependence | [13] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 8 Antagonist drugs | + | ||||
| 1 | Carbachol | Drug Info | [1] | |||
| 2 | Cisatracurium | Drug Info | [1], [14] | |||
| 3 | Levallorphan | Drug Info | [1] | |||
| 4 | Mivacurium | Drug Info | [14] | |||
| 5 | Pipecuronium | Drug Info | [1] | |||
| 6 | Rocuronium | Drug Info | [1], [14] | |||
| 7 | Tubocurarine | Drug Info | [1], [14] | |||
| 8 | Vecuronium | Drug Info | [1], [14] | |||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | CYTISINE | Drug Info | [15] | |||
| 2 | (S)-3-(azetidin-2-ylmethoxy)-2-fluoropyridine | Drug Info | [16] | |||
| 3 | 1,1-Dimethyl-4-phenyl-piperazin-1-ium iodide | Drug Info | [17] | |||
| 4 | 1-(piperidin-3-ylmethyl)pyridin-2(1H)-one | Drug Info | [15] | |||
| 5 | 1-(piperidin-4-ylmethyl)pyridin-2(1H)-one | Drug Info | [15] | |||
| 6 | 2-Pyridin-3-yl-7-aza-bicyclo[2.2.1]heptane | Drug Info | [18] | |||
| 7 | 3-((S)-Azetidin-2-yloxy)-5-iodo-pyridine | Drug Info | [17] | |||
| 8 | 5-(1-Methyl-pyrrolidin-2-yl)-2-phenethyl-pyridine | Drug Info | [19] | |||
| 9 | CHOLINE | Drug Info | [17] | |||
| Modulator (allosteric modulator) | [+] 1 Modulator (allosteric modulator) drugs | + | ||||
| 1 | LY2087101 | Drug Info | [20] | |||
| Agonist | [+] 2 Agonist drugs | + | ||||
| 1 | [125I]epibatidine | Drug Info | [21] | |||
| 2 | [3H]cytisine | Drug Info | [21] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Epibatidine | Ligand Info | |||||
| Structure Description | Crystal structure of the extracellular domain of alpha2 nicotinic acetylcholine receptor in pentameric assembly | PDB:5FJV | ||||
| Method | X-ray diffraction | Resolution | 3.20 Å | Mutation | No | [22] |
| PDB Sequence |
DRLFKHLFRG
43 YNRWARPVPN53 TSDVVIVRFG63 LSIAQLIDVD73 EKNQMMTTNV83 WLKQEWSDYK 93 LRWNPTDFGN103 ITSLRVPSEM113 IWIPDIVLYN123 NADGEFAVTH133 MTKAHLFSTG 143 TVHWVPPAIY153 KSSCSIDVTF163 FPFDQQNCKM173 KFGSWTYDKA183 KIDLEQMEQT 193 VDLKDYWESG203 EWAIVNATGT213 YNSKKYDCCA223 EIYPDVTYAF233 VIRRLPH |
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| 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 | |||||
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| Co-Targets | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Nicotinic acetylcholine receptor signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Highly calcium permeable postsynaptic nicotinic acetylcholine receptors | |||||
| 2 | Highly calcium permeable nicotinic acetylcholine receptors | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Synergy between pairs of competitive antagonists at adult human muscle acetylcholine receptors. Anesth Analg. 2008 Aug;107(2):525-33. | |||||
| REF 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: 298). | |||||
| REF 3 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 070292. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | 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: 7209). | |||||
| REF 6 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 010423. | |||||
| REF 7 | 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: 7243). | |||||
| REF 8 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
| REF 9 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 019638. | |||||
| REF 10 | 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: 2294). | |||||
| REF 11 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 005657. | |||||
| REF 12 | 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: 4002). | |||||
| REF 13 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 14 | Pharmacological characteristics of the inhibition of nondepolarizing neuromuscular blocking agents at human adult muscle nicotinic acetylcholine receptor. Anesthesiology. 2009 Jun;110(6):1244-52. | |||||
| REF 15 | Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity. J Med Chem. 2006 May 4;49(9):2673-6. | |||||
| REF 16 | Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of alpha4beta2 nicotinic acety... Bioorg Med Chem. 2009 Jul 1;17(13):4367-77. | |||||
| REF 17 | Pharmacology of the agonist binding sites of rat neuronal nicotinic receptor subtypes expressed in HEK 293 cells. Bioorg Med Chem Lett. 2004 Apr 19;14(8):1845-8. | |||||
| REF 18 | Epibatidine structure-activity relationships. Bioorg Med Chem Lett. 2004 Apr 19;14(8):1889-96. | |||||
| REF 19 | 6-(2-Phenylethyl)nicotine: a novel nicotinic cholinergic receptor ligand. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3237-40. | |||||
| REF 20 | Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006 Sep;318(3):1108-17. | |||||
| REF 21 | 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: 463). | |||||
| REF 22 | Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound Alpha2 homopentamer. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9635-40. | |||||
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