Target Information
| Target General Information | Top | |||||
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| Target ID |
T41580
(Former ID: TTDC00293)
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| Target Name |
Adrenergic receptor alpha-2B (ADRA2B)
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| Synonyms |
Subtype C2; Alpha-2BAR; Alpha-2B adrenoreceptor; Alpha-2B adrenoceptor; Alpha-2B adrenergic receptor; Alpha-2 adrenergic receptor subtype C2; ADRA2RL1; ADRA2L1
Click to Show/Hide
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| Gene Name |
ADRA2B
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Substance abuse [ICD-11: 6C40] | |||||
| Function |
The rank order of potency for agonists of this receptor is clonidine > norepinephrine > epinephrine = oxymetazoline > dopamine > p-tyramine = phenylephrine > serotonin > p-synephrine / p-octopamine. For antagonists, the rank order is yohimbine > chlorpromazine > phentolamine > mianserine > spiperone > prazosin > alprenolol > propanolol > pindolol. Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MDHQDPYSVQATAAIAAAITFLILFTIFGNALVILAVLTSRSLRAPQNLFLVSLAAADIL
VATLIIPFSLANELLGYWYFRRTWCEVYLALDVLFCTSSIVHLCAISLDRYWAVSRALEY NSKRTPRRIKCIILTVWLIAAVISLPPLIYKGDQGPQPRGRPQCKLNQEAWYILASSIGS FFAPCLIMILVYLRIYLIAKRSNRRGPRAKGGPGQGESKQPRPDHGGALASAKLPALASV ASAREVNGHSKSTGEKEEGETPEDTGTRALPPSWAALPNSGQGQKEGVCGASPEDEAEEE EEEEEEEEECEPQAVPVSPASACSPPLQQPQGSRVLATLRGQVLLGRGVGAIGGQWWRRR AQLTREKRFTFVLAVVIGVFVLCWFPFFFSYSLGAICPKHCKVPHGLFQFFFWIGYCNSS LNPVIYTIFNQDFRRAFRRILCRPWTQTAW Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T03GNH | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | MOXONIDINE | Drug Info | Approved | Alcohol dependence | [2] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | AGN-199981 | Drug Info | Phase 2 | Neuropathic pain | [3] | |
| 2 | MEDETOMIDINE | Drug Info | Phase 2 | Pain | [4] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | INDORAMIN | Drug Info | Withdrawn from market | Hypertension | [5], [6] | |
| 2 | SNAP-5089 | Drug Info | Terminated | Heart arrhythmia | [7], [8] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Inhibitor | [+] 59 Inhibitor drugs | + | ||||
| 1 | MOXONIDINE | Drug Info | [1] | |||
| 2 | MEDETOMIDINE | Drug Info | [9] | |||
| 3 | INDORAMIN | Drug Info | [10] | |||
| 4 | MAZAPERTINE | Drug Info | [11] | |||
| 5 | A-80426 | Drug Info | [12] | |||
| 6 | SK&F-104078 | Drug Info | [10] | |||
| 7 | SNAP-5089 | Drug Info | [13] | |||
| 8 | WB-4101 | Drug Info | [14] | |||
| 9 | (+/-)-nantenine | Drug Info | [15] | |||
| 10 | (1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol | Drug Info | [16] | |||
| 11 | (2-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 12 | (3-Ethyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 13 | (3-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 14 | (R)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [18] | |||
| 15 | (S)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [18] | |||
| 16 | 1',2',3',6'-Tetrahydro-[2,4']bipyridinyl | Drug Info | [19] | |||
| 17 | 1,2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline | Drug Info | [20] | |||
| 18 | 1,2,3,4,5,6-Hexahydro-benzo[c]azocine | Drug Info | [18] | |||
| 19 | 1,2,3,4-Tetrahydro-benzo[h]isoquinolin-8-ol | Drug Info | [21] | |||
| 20 | 1,2,3,4-Tetrahydro-isoquinolin-7-ol | Drug Info | [21] | |||
| 21 | 1,2,3,4-Tetrahydro-pyrazino[1,2-a]indole | Drug Info | [22] | |||
| 22 | 1,2,3,4-tetrahydroisoquinoline | Drug Info | [23] | |||
| 23 | 1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazine | Drug Info | [19] | |||
| 24 | 1-(pyridin-2-yl)piperazine | Drug Info | [19] | |||
| 25 | 2,3,4,5-Tetrahydro-1H-benzo[c]azepine | Drug Info | [18] | |||
| 26 | 2,3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine | Drug Info | [18] | |||
| 27 | 2,3,4,5-Tetrahydro-benzo[f][1,4]oxazepine | Drug Info | [18] | |||
| 28 | 2,3-Dihydro-1H-isoindole | Drug Info | [18] | |||
| 29 | 2-BFi | Drug Info | [24] | |||
| 30 | 3-Fluoromethyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [25] | |||
| 31 | 3-Methoxymethyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [16] | |||
| 32 | 3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [18] | |||
| 33 | 4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole | Drug Info | [9] | |||
| 34 | 4-(4-Methyl-indan-1-yl)-1H-imidazole | Drug Info | [26] | |||
| 35 | 4-Benzo[b]thiophen-4-yl-1H-imidazole | Drug Info | [27] | |||
| 36 | 5-Aminomethyl-naphthalen-2-ol | Drug Info | [21] | |||
| 37 | 6,7,8,9-Tetrahydro-5-thia-8-aza-benzocycloheptene | Drug Info | [18] | |||
| 38 | 7-Methoxy-2,3,4,9-tetrahydro-1H-beta-carboline | Drug Info | [28] | |||
| 39 | 8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline | Drug Info | [21] | |||
| 40 | Butyl-indol-1-yl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 41 | C-(6-Methoxy-naphthalen-1-yl)-methylamine | Drug Info | [21] | |||
| 42 | C-Naphthalen-1-yl-methylamine | Drug Info | [21] | |||
| 43 | Ethyl-indol-1-yl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 44 | GNF-PF-2857 | Drug Info | [29] | |||
| 45 | GNF-PF-3878 | Drug Info | [29] | |||
| 46 | Indol-1-yl-methyl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 47 | Indol-1-yl-prop-2-ynyl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 48 | Indol-1-yl-pyridin-4-yl-amine | Drug Info | [17] | |||
| 49 | JP1302 | Drug Info | [29] | |||
| 50 | METHYLNORADRENALINE | Drug Info | [14] | |||
| 51 | MEZILAMINE | Drug Info | [31] | |||
| 52 | PIPEROXAN | Drug Info | [14] | |||
| 53 | R-226161 | Drug Info | [32] | |||
| 54 | S-34324 | Drug Info | [12] | |||
| 55 | SK&F-64139 | Drug Info | [23] | |||
| 56 | SNAP-5150 | Drug Info | [13] | |||
| 57 | TRACIZOLINE | Drug Info | [28] | |||
| 58 | Tramazoline | Drug Info | [14] | |||
| 59 | TRYPTOLINE | Drug Info | [28] | |||
| Agonist | [+] 2 Agonist drugs | + | ||||
| 1 | AGN-199981 | Drug Info | [3] | |||
| 2 | xylazine | Drug Info | [34] | |||
| Antagonist | [+] 5 Antagonist drugs | + | ||||
| 1 | imiloxan | Drug Info | [30] | |||
| 2 | spiroxatrine | Drug Info | [33] | |||
| 3 | [3H]MK-912 | Drug Info | [33] | |||
| 4 | [3H]rauwolscine | Drug Info | [35] | |||
| 5 | [3H]RX821002 | Drug Info | [36], [37] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| 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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| cGMP-PKG signaling pathway | hsa04022 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| 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 Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | cGMP-PKG signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Alpha adrenergic receptor signaling pathway | |||||
| 2 | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | Adrenoceptors | |||||
| 2 | Adrenaline signalling through Alpha-2 adrenergic receptor | |||||
| 3 | G alpha (i) signalling events | |||||
| 4 | G alpha (z) signalling events | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Monoamine GPCRs | |||||
| 2 | GPCRs, Class A Rhodopsin-like | |||||
| 3 | Platelet Aggregation (Plug Formation) | |||||
| 4 | GPCR ligand binding | |||||
| 5 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent. J Med Chem. 1996 Mar 15;39(6):1193-5. | |||||
| REF 2 | The role of I(1)-imidazoline and alpha(2)-adrenergic receptors in the modulation of glucose metabolism in the spontaneously hypertensive obese rat ... J Pharmacol Exp Ther. 2003 Aug;306(2):646-57. | |||||
| REF 3 | Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26. | |||||
| REF 4 | Sedative and cardiopulmonary effects of medetomidine hydrochloride and xylazine hydrochloride and their reversal with atipamezole hydrochloride in calves. Am J Vet Res. 2008 Mar;69(3):319-29. | |||||
| 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: 501). | |||||
| REF 6 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| 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: 498). | |||||
| REF 8 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771) | |||||
| REF 9 | A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic recep... J Med Chem. 1994 Jul 22;37(15):2328-33. | |||||
| REF 10 | Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification. J Med Chem. 1995 Sep 1;38(18):3415-44. | |||||
| REF 11 | A new arylpiperazine antipsychotic with high D2/D3/5-HT1A/alpha 1A-adrenergic affinity and a low potential for extrapyramidal effects. J Med Chem. 1994 Apr 15;37(8):1060-2. | |||||
| REF 12 | Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking... J Med Chem. 2005 Mar 24;48(6):2054-71. | |||||
| REF 13 | Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8. | |||||
| REF 14 | alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs. J Med Chem. 1982 Dec;25(12):1389-401. | |||||
| REF 15 | Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. | |||||
| REF 16 | 3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and selectivity as inhibitors of phenylethanolamine N-methyltransferas... J Med Chem. 1999 Jun 3;42(11):1982-90. | |||||
| REF 17 | Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeu... J Med Chem. 1996 Jan 19;39(2):570-81. | |||||
| REF 18 | Effect of ring size or an additional heteroatom on the potency and selectivity of bicyclic benzylamine-type inhibitors of phenylethanolamine N-meth... J Med Chem. 1996 Aug 30;39(18):3539-46. | |||||
| REF 19 | Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines. J Med Chem. 1984 Sep;27(9):1182-5. | |||||
| REF 20 | N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies. J Med Chem. 1998 Oct 8;41(21):4165-70. | |||||
| REF 21 | Examination of the role of the acidic hydrogen in imparting selectivity of 7-(aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) toward inh... J Med Chem. 1997 Dec 5;40(25):3997-4005. | |||||
| REF 22 | Pyrazino[1,2-a]indoles as novel high-affinity and selective imidazoline I(2) receptor ligands. Bioorg Med Chem Lett. 2004 Feb 23;14(4):1003-5. | |||||
| REF 23 | Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phen... J Med Chem. 2006 Sep 7;49(18):5424-33. | |||||
| REF 24 | Probes for imidazoline binding sites: synthesis and evaluation of a selective, irreversible I2 ligand. Bioorg Med Chem Lett. 2000 Mar 20;10(6):605-7. | |||||
| REF 25 | 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline inhibitors of phenylethanolamine N-methyltransferase that display re... J Med Chem. 2005 Jan 13;48(1):134-40. | |||||
| REF 26 | Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potent... J Med Chem. 1997 Sep 12;40(19):3014-24. | |||||
| REF 27 | alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a ... J Med Chem. 2000 Mar 9;43(5):765-8. | |||||
| REF 28 | Binding of an imidazopyridoindole at imidazoline I2 receptors. Bioorg Med Chem Lett. 2004 Jan 19;14(2):527-9. | |||||
| REF 29 | Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists. J Med Chem. 2006 Oct 19;49(21):6351-63. | |||||
| REF 30 | Assessment of imiloxan as a selective alpha 2B-adrenoceptor antagonist. Br J Pharmacol. 1990 Mar;99(3):560-4. | |||||
| REF 31 | 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors. J Med Chem. 1986 Aug;29(8):1394-8. | |||||
| REF 32 | Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-a... Bioorg Med Chem. 2007 Jun 1;15(11):3649-60. | |||||
| REF 33 | The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. J Pharmacol Exp Ther. 1994 Dec;271(3):1558-65. | |||||
| REF 34 | Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding. Biochem Pharmacol. 1998 Apr 1;55(7):1035-43. | |||||
| REF 35 | Pharmacological characteristics of alpha 2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol. 1992 Jul;42(1):1-5. | |||||
| REF 36 | Further characterization of human alpha 2-adrenoceptor subtypes: [3H]RX821002 binding and definition of additional selective drugs. Eur J Pharmacol. 1994 Jan 24;252(1):43-9. | |||||
| REF 37 | Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists. J Med Chem. 1986 Oct;29(10):2000-3. | |||||
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