Target Information
| Target General Information | Top | |||||
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| Target ID |
T82543
(Former ID: TTDC00301)
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| Target Name |
Neuronal acetylcholine receptor beta-2 (CHRNB2)
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| Synonyms |
Nicotinic acetylcholine receptor beta2; Nicotinic acetylcholine receptor beta 2-subunit protein; CHRNB2; Beta-2 nAChR; Alpha-4/beta-2 nicotinic receptor
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| Gene Name |
CHRNB2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Nicotine use disorder [ICD-11: 6C4A] | |||||
| 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 permeable to sodiun ions.
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| BioChemical Class |
Neurotransmitter receptor
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| UniProt ID | ||||||
| Sequence |
MARRCGPVALLLGFGLLRLCSGVWGTDTEERLVEHLLDPSRYNKLIRPATNGSELVTVQL
MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLY NNADGMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDR TEIDLVLKSEVASLDDFTPSGEWDIVALPGRRNENPDDSTYVDITYDFIIRRKPLFYTIN LIIPCVLITSLAILVFYLPSDCGEKMTLCISVLLALTVFLLLISKIVPPTSLDVPLVGKY LMFTMVLVTFSIVTSVCVLNVHHRSPTTHTMAPWVKVVFLEKLPALLFMQQPRHHCARQR LRLRRRQREREGAGALFFREAPGADSCTCFVNRASVQGLAGAFGAEPAPVAGPGRSGEPC GCGLREAVDGVRFIADHMRSEDDDQSVSEDWKYVAMVIDRLFLWIFVFVCVFGTIGMFLQ PLFQNYTTTTFLHSDHSAPSSK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | CYTISINE | Drug Info | Phase 3 | Tobacco dependence | [2] | |
| 2 | TC-5214 | Drug Info | Phase 2 | Palmar hyperhidrosis | [3] | |
| 3 | SUVN-911 | Drug Info | Phase 1 | Major depressive disorder | [2] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | ABT-418 | Drug Info | Discontinued in Phase 2 | Alzheimer disease | [4] | |
| 2 | AZD-9684 | Drug Info | Discontinued in Phase 2 | Thrombosis | [5] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Inhibitor | [+] 19 Inhibitor drugs | + | ||||
| 1 | CYTISINE | Drug Info | [1] | |||
| 2 | HOMOEPIBATIDINE | Drug Info | [1] | |||
| 3 | (2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol | Drug Info | [10] | |||
| 4 | (2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol | Drug Info | [10] | |||
| 5 | 3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine | Drug Info | [11] | |||
| 6 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [12] | |||
| 7 | 6'-methylepibatidine | Drug Info | [13] | |||
| 8 | BOLDINE | Drug Info | [15] | |||
| 9 | CMI-489 | Drug Info | [13] | |||
| 10 | GCCSHPACAGNNQHIC* | Drug Info | [16] | |||
| 11 | GCCSNPVCHLEHSNLC* | Drug Info | [16] | |||
| 12 | N,N-dimethyl(pyridin-3-yl)methanamine | Drug Info | [18] | |||
| 13 | N,N-dimethyl-2-(pyridin-3-yloxy)ethanamine | Drug Info | [18] | |||
| 14 | N,N-dimethyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [18] | |||
| 15 | N-ethyl-N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [18] | |||
| 16 | N-methyl-2-(pyridin-3-yloxy)ethanamine | Drug Info | [18] | |||
| 17 | N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine | Drug Info | [18] | |||
| 18 | N-methyl-N-(pyridin-3-ylmethyl)ethanamine | Drug Info | [18] | |||
| 19 | Predicentrine methiodide | Drug Info | [15] | |||
| Antagonist | [+] 3 Antagonist drugs | + | ||||
| 1 | TC-5214 | Drug Info | [3] | |||
| 2 | SUVN-911 | Drug Info | [2] | |||
| 3 | AZD-9684 | Drug Info | [9] | |||
| Agonist | [+] 6 Agonist drugs | + | ||||
| 1 | ABT-418 | Drug Info | [6], [7] | |||
| 2 | ABT-594 | Drug Info | [8] | |||
| 3 | TC-2559 | Drug Info | [21] | |||
| 4 | [125I]epibatidine | Drug Info | [22] | |||
| 5 | [3H]cytisine | Drug Info | [22] | |||
| 6 | [3H]nicotine | Drug Info | [22] | |||
| Blocker (channel blocker) | [+] 2 Blocker (channel blocker) drugs | + | ||||
| 1 | A-867744 | Drug Info | [14] | |||
| 2 | NS1738 | Drug Info | [19] | |||
| Modulator (allosteric modulator) | [+] 2 Modulator (allosteric modulator) drugs | + | ||||
| 1 | LY2087101 | Drug Info | [17] | |||
| 2 | NS9283 | Drug Info | [20] | |||
| 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: Nicotine | Ligand Info | |||||
| Structure Description | Structure of the 2alpha3beta stiochiometry of the human Alpha4Beta2 nicotinic receptor | PDB:6CNJ | ||||
| Method | Electron microscopy | Resolution | 3.70 Å | Mutation | No | [23] |
| PDB Sequence |
DTEERLVEHL
11 LDPSRYNKLI21 RPATNGSELV31 TVQLMVSLAQ41 LISVHEREQI51 MTTNVWLTQE 61 WEDYRLTWKP71 EEFDNMKKVR81 LPSKHIWLPD91 VVLYNNADGM101 YEVSFYSNAV 111 VSYDGSIFWL121 PPAIYKSACK131 IEVKHFPFDQ141 QNCTMKFRSW151 TYDRTEIDLV 161 LKSEVASLDD171 FTPSGEWDIV181 ALPGRRNENP191 DDSTYVDITY201 DFIIRRKPLF 211 YTINLIIPCV221 LITSLAILVF231 YLPSDCGEKM241 TLCISVLLAL251 TVFLLLISKI 261 VPPTSLDVPL271 VGKYLMFTMV281 LVTFSIVTSV291 CVLNVHHRSP301 TTHTMAPWVK 311 VVFLEKLPAL321 LFMQQSVSED341 WKYVAMVIDR351 LFLWIFVFVC361 VFGTIGMF |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Varenicline | Ligand Info | |||||
| Structure Description | CryoEM structure of human alpha4beta2 nicotinic acetylcholine receptor in complex with varenicline | PDB:6UR8 | ||||
| Method | Electron microscopy | Resolution | 3.71 Å | Mutation | No | [24] |
| PDB Sequence |
DTEERLVEHL
11 LDPSRYNKLI21 RPATNGSELV31 TVQLMVSLAQ41 LISVHEREQI51 MTTNVWLTQE 61 WEDYRLTWKP71 EEFDNMKKVR81 LPSKHIWLPD91 VVLYNNADGM101 YEVSFYSNAV 111 VSYDGSIFWL121 PPAIYKSACK131 IEVKHFPFDQ141 QNCTMKFRSW151 TYDRTEIDLV 161 LKSEVASLDD171 FTPSGEWDIV181 ALPGRRNENP191 DDSTYVDITY201 DFIIRRKPLF 211 YTINLIIPCV221 LITSLAILVF231 YLPSDCGEKM241 TLCISVLLAL251 TVFLLLISKI 261 VPPTSLDVPL271 VGKYLMFTMV281 LVTFSIVTSV291 CVLNVHHRSP301 TTHTMAPWVK 311 VVFLEKLPAL321 LFMQQSVSED337 WKYVAMVIDR347 LFLWIFVFVC357 VFGTIGMF |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| 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).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Pathway Affiliation
Biological Network Descriptors
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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 | ||
| Cholinergic synapse | hsa04725 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.07E-04 | Radiality | 3.98E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+00 | Topological coefficient | . | Eccentricity | 1 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 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 | Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | 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 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018349) | |||||
| REF 6 | Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. Arch Med Res. 2000 Mar-Apr;31(2):131-44. | |||||
| REF 7 | (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 8 | 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 9 | Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001 Apr;94(4):643-51. | |||||
| REF 10 | 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 11 | Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4283-6. | |||||
| REF 12 | 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 13 | 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 14 | In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methy... J Pharmacol Exp Ther. 2009 Jul;330(1):257-67. | |||||
| REF 15 | Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72. | |||||
| REF 16 | Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45. | |||||
| REF 17 | 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 18 | 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. | |||||
| REF 19 | An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther. 2007 Oct;323(1):294-307. | |||||
| REF 20 | alpha4beta2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of alpha4beta2 nAChR agonists in pain. Biochem Pharmacol. 2011 Oct 15;82(8):959-66. | |||||
| REF 21 | The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices. Neuropharmacology. 2003 Sep;45(3):334-44. | |||||
| REF 22 | 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: 465). | |||||
| REF 23 | Structural principles of distinct assemblies of the human Alpha4beta2 nicotinic receptor. Nature. 2018 May;557(7704):261-265. | |||||
| REF 24 | Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins. Nat Commun. 2020 Mar 27;11(1):1598. | |||||
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