Target Information

Target General Infomation
Target ID
T41580
Former ID
TTDC00293
Target Name
Alpha-2B adrenergic receptor
Gene Name
ADRA2B
Synonyms
Alpha-2B adrenoceptor; Alpha-2B adrenoreceptor; Subtype C2; ADRA2B
Target Type
Successful
Disease Alcohol use disorders [ICD9: 303; ICD10: F10.2]
Hypertension [ICD9: 401; ICD10: I10-I16]
Heart arrhythmia [ICD10: I47-I49]
Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Function
Alpha-2 adrenergic receptors mediate the catecholamine- induced inhibition of adenylate cyclase through the action of G proteins. 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.
BioChemical Class
GPCR rhodopsin
Target Validation
T41580
UniProt ID
P18089
Sequence
MDHQDPYSVQATAAIAAAITFLILFTIFGNALVILAVLTSRSLRAPQNLFLVSLAAADIL
VATLIIPFSLANELLGYWYFRRTWCEVYLALDVLFCTSSIVHLCAISLDRYWAVSRALEY
NSKRTPRRIKCIILTVWLIAAVISLPPLIYKGDQGPQPRGRPQCKLNQEAWYILASSIGS
FFAPCLIMILVYLRIYLIAKRSNRRGPRAKGGPGQGESKQPRPDHGGALASAKLPALASV
ASAREVNGHSKSTGEKEEGETPEDTGTRALPPSWAALPNSGQGQKEGVCGASPEDEAEEE
EEEEEEEEECEPQAVPVSPASACSPPLQQPQGSRVLATLRGQVLLGRGVGAIGGQWWRRR
AQLTREKRFTFVLAVVIGVFVLCWFPFFFSYSLGAICPKHCKVPHGLFQFFFWIGYCNSS
LNPVIYTIFNQDFRRAFRRILCRPWTQTAW
Drugs and Mode of Action
Drug(s) MOXONIDINE Drug Info Approved Alcohol use disorders [526626]
AGN-199981 Drug Info Phase 2 Neuropathic pain [536374]
MEDETOMIDINE Drug Info Phase 2 Pain [529347]
INDORAMIN Drug Info Withdrawn from market Hypertension [468125], [551871]
MAZAPERTINE Drug Info Discontinued in Phase 2 Discovery agent [545274]
A-80426 Drug Info Terminated Discovery agent [546043]
SK&F-104078 Drug Info Terminated Discovery agent [544626]
SNAP-5089 Drug Info Terminated Heart arrhythmia [468115], [546179]
WB-4101 Drug Info Terminated Discovery agent [468117], [545656]
Inhibitor (+/-)-nantenine Drug Info [530558]
(1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol Drug Info [525507]
(2-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine Drug Info [534087]
(3-Ethyl-indol-1-yl)-propyl-pyridin-4-yl-amine Drug Info [534087]
(3-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine Drug Info [534087]
(R)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline Drug Info [534195]
(S)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline Drug Info [534195]
1',2',3',6'-Tetrahydro-[2,4']bipyridinyl Drug Info [533509]
1,2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline Drug Info [534719]
1,2,3,4,5,6-Hexahydro-benzo[c]azocine Drug Info [534195]
1,2,3,4-Tetrahydro-benzo[h]isoquinolin-8-ol Drug Info [534531]
1,2,3,4-Tetrahydro-isoquinolin-7-ol Drug Info [534531]
1,2,3,4-Tetrahydro-pyrazino[1,2-a]indole Drug Info [526994]
1,2,3,4-tetrahydroisoquinoline Drug Info [528403]
1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazine Drug Info [533509]
1-(pyridin-2-yl)piperazine Drug Info [533509]
2,3,4,5-Tetrahydro-1H-benzo[c]azepine Drug Info [534195]
2,3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine Drug Info [534195]
2,3,4,5-Tetrahydro-benzo[f][1,4]oxazepine Drug Info [534195]
2,3-Dihydro-1H-isoindole Drug Info [534195]
2-BFi Drug Info [525733]
3-Fluoromethyl-1,2,3,4-tetrahydro-isoquinoline Drug Info [527365]
3-Methoxymethyl-1,2,3,4-tetrahydro-isoquinoline Drug Info [525507]
3-Methyl-1,2,3,4-tetrahydro-isoquinoline Drug Info [534195]
4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole Drug Info [533805]
4-(4-Methyl-indan-1-yl)-1H-imidazole Drug Info [534467]
4-Benzo[b]thiophen-4-yl-1H-imidazole Drug Info [525720]
5-Aminomethyl-naphthalen-2-ol Drug Info [534531]
6,7,8,9-Tetrahydro-5-thia-8-aza-benzocycloheptene Drug Info [534195]
7-Methoxy-2,3,4,9-tetrahydro-1H-beta-carboline Drug Info [526918]
8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline Drug Info [534531]
A-80426 Drug Info [527481]
Butyl-indol-1-yl-pyridin-4-yl-amine Drug Info [534087]
C-(6-Methoxy-naphthalen-1-yl)-methylamine Drug Info [534531]
C-Naphthalen-1-yl-methylamine Drug Info [534531]
Ethyl-indol-1-yl-pyridin-4-yl-amine Drug Info [534087]
GNF-PF-2857 Drug Info [528472]
GNF-PF-3427 Drug Info [528472]
GNF-PF-3878 Drug Info [528472]
Indol-1-yl-methyl-pyridin-4-yl-amine Drug Info [534087]
Indol-1-yl-prop-2-ynyl-pyridin-4-yl-amine Drug Info [534087]
Indol-1-yl-propyl-pyridin-4-yl-amine Drug Info [534087]
Indol-1-yl-pyridin-4-yl-amine Drug Info [534087]
INDORAMIN Drug Info [533682]
MAZAPERTINE Drug Info [533800]
MEDETOMIDINE Drug Info [533805]
METHYLNORADRENALINE Drug Info [533545]
MEZILAMINE Drug Info [533406]
MOXONIDINE Drug Info [534128]
PIPEROXAN Drug Info [533545]
R-226161 Drug Info [528772]
RX-821002 Drug Info [533375]
S-34324 Drug Info [527481]
SK&F-104078 Drug Info [533682]
SK&F-64139 Drug Info [528403]
SNAP-5089 Drug Info [525611]
SNAP-5150 Drug Info [525611]
TRACIZOLINE Drug Info [526918]
TRAMAZOLINE Drug Info [533545]
TRYPTOLINE Drug Info [526918]
WB-4101 Drug Info [533545]
Agonist AGN-199981 Drug Info [536374]
xylazine Drug Info [534634]
Antagonist imiloxan Drug Info [530335]
spiroxatrine Drug Info [533843]
[3H]MK-912 Drug Info [533843]
[3H]rauwolscine Drug Info [526770]
[3H]RX821002 Drug Info [533799]
Pathways
KEGG Pathway cGMP-PKG signaling pathway
Neuroactive ligand-receptor interaction
PANTHER Pathway Alpha adrenergic receptor signaling pathway
Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Reactome Adrenoceptors
Adrenaline signalling through Alpha-2 adrenergic receptor
G alpha (i) signalling events
G alpha (z) signalling events
WikiPathways Monoamine GPCRs
GPCRs, Class A Rhodopsin-like
Platelet Aggregation (Plug Formation)
GPCR ligand binding
GPCR downstream signaling
References
Ref 468115(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 468117(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: 499).
Ref 468125(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 526626The role of I(1)-imidazoline and alpha(2)-adrenergic receptors in the modulation of glucose metabolism in the spontaneously hypertensive obese rat model of metabolic syndrome X. J Pharmacol Exp Ther.2003 Aug;306(2):646-57. Epub 2003 May 19.
Ref 529347Sedative 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 536374Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
Ref 544626Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000354)
Ref 545274Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002662)
Ref 545656Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004048)
Ref 546043Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006017)
Ref 546179Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006771)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 525507J Med Chem. 1999 Jun 3;42(11):1982-90.3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines display remarkable potency and selectivity as inhibitors of phenylethanolamine N-methyltransferase versus the alpha2-adrenoceptor.
Ref 525611Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8.Design and synthesis of novel dihydropyridine alpha-1a antagonists.
Ref 525720J Med Chem. 2000 Mar 9;43(5):765-8.alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Ref 525733Bioorg Med Chem Lett. 2000 Mar 20;10(6):605-7.Probes for imidazoline binding sites: synthesis and evaluation of a selective, irreversible I2 ligand.
Ref 526770Pharmacological 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 526918Bioorg Med Chem Lett. 2004 Jan 19;14(2):527-9.Binding of an imidazopyridoindole at imidazoline I2 receptors.
Ref 526994Bioorg Med Chem Lett. 2004 Feb 23;14(4):1003-5.Pyrazino[1,2-a]indoles as novel high-affinity and selective imidazoline I(2) receptor ligands.
Ref 527365J Med Chem. 2005 Jan 13;48(1):134-40.3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline inhibitors of phenylethanolamine N-methyltransferase that display remarkable potency and selectivity.
Ref 527481J Med Chem. 2005 Mar 24;48(6):2054-71.Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking activity.
Ref 528403J Med Chem. 2006 Sep 7;49(18):5424-33.Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamineN-methyltransferase.
Ref 528472J Med Chem. 2006 Oct 19;49(21):6351-63.Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists.
Ref 528772Bioorg Med Chem. 2007 Jun 1;15(11):3649-60. Epub 2007 Mar 21.Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-adrenoceptor antagonism.
Ref 530335Assessment of imiloxan as a selective alpha 2B-adrenoceptor antagonist. Br J Pharmacol. 1990 Mar;99(3):560-4.
Ref 530558Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.
Ref 533375J Med Chem. 1986 Oct;29(10):2000-3.Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists.
Ref 533406J Med Chem. 1986 Aug;29(8):1394-8.4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors.
Ref 533509J Med Chem. 1984 Sep;27(9):1182-5.Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.
Ref 533545J Med Chem. 1982 Dec;25(12):1389-401.alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs.
Ref 533682J Med Chem. 1995 Sep 1;38(18):3415-44.Alpha- and beta-adrenoceptors: from the gene to the clinic. 1. Molecular biology and adrenoceptor subclassification.
Ref 533799Further 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 533800J Med Chem. 1994 Apr 15;37(8):1060-2.A new arylpiperazine antipsychotic with high D2/D3/5-HT1A/alpha 1A-adrenergic affinity and a low potential for extrapyramidal effects.
Ref 533805J Med Chem. 1994 Jul 22;37(15):2328-33.A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.
Ref 533843The 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 534087J Med Chem. 1996 Jan 19;39(2):570-81.Synthesis and structure-activity relationships of N-propyl-N-(4-pyridinyl)-1H-indol-1-amine (besipirdine) and related analogs as potential therapeutic agents for Alzheimer's disease.
Ref 534128J Med Chem. 1996 Mar 15;39(6):1193-5.Synthesis and pharmacologic evaluation of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane: a potent imidazoline1 receptor specific agent.
Ref 534195J Med Chem. 1996 Aug 30;39(18):3539-46.Effect of ring size or an additional heteroatom on the potency and selectivity of bicyclic benzylamine-type inhibitors of phenylethanolamine N-methyltransferase.
Ref 534467J Med Chem. 1997 Sep 12;40(19):3014-24.Medetomidine analogs as alpha 2-adrenergic ligands. 3. Synthesis and biological evaluation of a new series of medetomidine analogs and their potential binding interactions with alpha 2-adrenoceptors involving a "methyl pocket".
Ref 534531J Med Chem. 1997 Dec 5;40(25):3997-4005.Examination of the role of the acidic hydrogen in imparting selectivity of 7-(aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) toward inhibition of phenylethanolamine N-methyltransferase vs the alpha 2-adrenoceptor.
Ref 534634Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding. Biochem Pharmacol. 1998 Apr 1;55(7):1035-43.
Ref 534719J Med Chem. 1998 Oct 8;41(21):4165-70.N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies.
Ref 536374Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.

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