Target Information
Target General Information | Top | |||||
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Target ID |
T11448
(Former ID: TTDS00032)
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Target Name |
Adrenergic receptor alpha-2A (ADRA2A)
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Synonyms |
Alpha-2AAR; Alpha-2A adrenoreceptor; Alpha-2A adrenoceptor; Alpha-2A adrenergic receptor; Alpha-2 adrenergic receptor subtype C10; ADRAR; ADRA2R
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Gene Name |
ADRA2A
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 3 Target-related Diseases | + | ||||
1 | Attention deficit hyperactivity disorder [ICD-11: 6A05] | |||||
2 | Opioid use disorder [ICD-11: 6C43] | |||||
3 | Substance abuse [ICD-11: 6C40] | |||||
Function |
The rank order of potency for agonists of this receptor is oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianserine > chlorpromazine = spiperone = prazosin > propanolol > alprenolol = 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 |
MFRQEQPLAEGSFAPMGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLML
LTVFGNVLVIIAVFTSRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAW CEIYLALDVLFCTSSIVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVIS FPPLISIEKKGGGGGPQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKR RTRVPPSRRGPDAVAAPPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGP RDTDALDLEESSSSDHAERPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTP AAGPGEERVGAAKASRWRGRQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPR TLFKFFFWFGYCNSSLNPVIYTIFNHDFRRAFKKILCRGDRKRIV Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
ADReCS ID | BADD_A00273 ; BADD_A05198 ; BADD_A06414 ; BADD_A08478 ; BADD_A08611 | |||||
HIT2.0 ID | T77RFX |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
1 | Connexyn | Drug Info | Approved | Attention deficit hyperactivity disorder | [2] | |
2 | Lofexidine | Drug Info | Approved | Opioid dependence | [3] | |
3 | MOXONIDINE | Drug Info | Approved | Alcohol dependence | [4] | |
Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | MEDETOMIDINE | Drug Info | Phase 2 | Pain | [5] | |
2 | DSP-1200 | Drug Info | Phase 1 | Depression | [6] | |
Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
1 | NMI-870 | Drug Info | Discontinued in Phase 2 | Sexual dysfunction | [7] | |
2 | S-18616 | Drug Info | Terminated | Pain | [8] | |
3 | SNAP-5089 | Drug Info | Terminated | Heart arrhythmia | [9], [10] | |
Mode of Action | [+] 4 Modes of Action | + | ||||
Agonist | [+] 4 Agonist drugs | + | ||||
1 | Connexyn | Drug Info | [1] | |||
2 | Lofexidine | Drug Info | [3] | |||
3 | Beta-methoxyamphetamine | Drug Info | [40] | |||
4 | Chloroethylclonidine | Drug Info | [43] | |||
Inhibitor | [+] 70 Inhibitor drugs | + | ||||
1 | MOXONIDINE | Drug Info | [11] | |||
2 | MEDETOMIDINE | Drug Info | [12] | |||
3 | MAZAPERTINE | Drug Info | [13] | |||
4 | A-80426 | Drug Info | [15] | |||
5 | SK&F-104078 | Drug Info | [17] | |||
6 | SNAP-5089 | Drug Info | [18] | |||
7 | WB-4101 | Drug Info | [19] | |||
8 | (+/-)-nantenine | Drug Info | [20] | |||
9 | (1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol | Drug Info | [21] | |||
10 | (1H-Benzoimidazol-5-yl)-(1H-imidazol-2-yl)-amine | Drug Info | [22] | |||
11 | (1H-Imidazol-2-yl)-quinoxalin-6-yl-amine | Drug Info | [22] | |||
12 | (2,6-Dichloro-phenyl)-(1H-imidazol-2-yl)-amine | Drug Info | [22] | |||
13 | (2-Bromo-phenyl)-(1H-imidazol-2-yl)-amine | Drug Info | [22] | |||
14 | (2-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [23] | |||
15 | (3-Ethyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [23] | |||
16 | (3-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine | Drug Info | [23] | |||
17 | (R)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [24] | |||
18 | (S)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [24] | |||
19 | 1',2',3',6'-Tetrahydro-[2,4']bipyridinyl | Drug Info | [25] | |||
20 | 1,2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline | Drug Info | [26] | |||
21 | 1,2,3,4,5,6-Hexahydro-benzo[c]azocine | Drug Info | [24] | |||
22 | 1,2,3,4-Tetrahydro-benzo[h]isoquinolin-8-ol | Drug Info | [27] | |||
23 | 1,2,3,4-Tetrahydro-isoquinolin-7-ol | Drug Info | [27] | |||
24 | 1,2,3,4-Tetrahydro-pyrazino[1,2-a]indole | Drug Info | [28] | |||
25 | 1,2,3,4-tetrahydroisoquinoline | Drug Info | [29] | |||
26 | 1-((S)-2-aminopropyl)-1H-indazol-6-ol | Drug Info | [30] | |||
27 | 1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazine | Drug Info | [25] | |||
28 | 1-(pyridin-2-yl)piperazine | Drug Info | [25] | |||
29 | 2,3,4,5-Tetrahydro-1H-benzo[c]azepine | Drug Info | [24] | |||
30 | 2,3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine | Drug Info | [24] | |||
31 | 2,3,4,5-Tetrahydro-benzo[f][1,4]oxazepine | Drug Info | [24] | |||
32 | 2,3-Dihydro-1H-isoindole | Drug Info | [24] | |||
33 | 2-BFi | Drug Info | [31] | |||
34 | 3-Fluoromethyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [32] | |||
35 | 3-Methoxymethyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [21] | |||
36 | 3-Methyl-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [24] | |||
37 | 3-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [33] | |||
38 | 4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole | Drug Info | [12] | |||
39 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [34] | |||
40 | 4-(4-Methyl-indan-1-yl)-1H-imidazole | Drug Info | [35] | |||
41 | 4-Benzo[b]thiophen-4-yl-1H-imidazole | Drug Info | [36] | |||
42 | 5-Aminomethyl-naphthalen-2-ol | Drug Info | [27] | |||
43 | 6,7,8,9-Tetrahydro-5-thia-8-aza-benzocycloheptene | Drug Info | [24] | |||
44 | 7-Methoxy-2,3,4,9-tetrahydro-1H-beta-carboline | Drug Info | [37] | |||
45 | 7-Nitro-1,2,3,4-tetrahydro-isoquinoline | Drug Info | [33] | |||
46 | 8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline | Drug Info | [27] | |||
47 | AKUAMMIGINE | Drug Info | [38] | |||
48 | AR-129330 | Drug Info | [39] | |||
49 | Butyl-indol-1-yl-pyridin-4-yl-amine | Drug Info | [23] | |||
50 | C-(6-Methoxy-naphthalen-1-yl)-methylamine | Drug Info | [27] | |||
51 | C-Naphthalen-1-yl-methylamine | Drug Info | [27] | |||
52 | Ethyl-indol-1-yl-pyridin-4-yl-amine | Drug Info | [23] | |||
53 | GNF-PF-2857 | Drug Info | [45] | |||
54 | GNF-PF-3878 | Drug Info | [45] | |||
55 | Indol-1-yl-methyl-pyridin-4-yl-amine | Drug Info | [23] | |||
56 | Indol-1-yl-prop-2-ynyl-pyridin-4-yl-amine | Drug Info | [23] | |||
57 | Indol-1-yl-pyridin-4-yl-amine | Drug Info | [23] | |||
58 | JP1302 | Drug Info | [45] | |||
59 | METHYLNORADRENALINE | Drug Info | [19] | |||
60 | MEZILAMINE | Drug Info | [46] | |||
61 | PIPEROXAN | Drug Info | [19] | |||
62 | R-226161 | Drug Info | [47] | |||
63 | S-34324 | Drug Info | [15] | |||
64 | SK&F-29661 | Drug Info | [33] | |||
65 | SK&F-64139 | Drug Info | [29] | |||
66 | SNAP-5150 | Drug Info | [18] | |||
67 | TRACIZOLINE | Drug Info | [37] | |||
68 | Tramazoline | Drug Info | [19] | |||
69 | TRYPTOLINE | Drug Info | [37] | |||
70 | [3H]RX821002 | Drug Info | [48] | |||
Antagonist | [+] 3 Antagonist drugs | + | ||||
1 | DSP-1200 | Drug Info | [6] | |||
2 | BRL 44408 | Drug Info | [41], [42] | |||
3 | Ciproxifan | Drug Info | [44] | |||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | NMI-870 | Drug Info | [14] | |||
2 | S-18616 | Drug Info | [16] |
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 | [+] 1 Panther Pathways | + | ||||
1 | Alpha adrenergic receptor signaling pathway | |||||
Reactome | [+] 6 Reactome Pathways | + | ||||
1 | Adrenoceptors | |||||
2 | Adrenaline signalling through Alpha-2 adrenergic receptor | |||||
3 | Adrenaline,noradrenaline inhibits insulin secretion | |||||
4 | G alpha (i) signalling events | |||||
5 | G alpha (z) signalling events | |||||
6 | Surfactant metabolism | |||||
WikiPathways | [+] 6 WikiPathways | + | ||||
1 | Monoamine GPCRs | |||||
2 | GPCRs, Class A Rhodopsin-like | |||||
3 | Platelet Aggregation (Plug Formation) | |||||
4 | Integration of energy metabolism | |||||
5 | GPCR ligand binding | |||||
6 | GPCR downstream signaling |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | alpha2A-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuroscience. 2009 Sep 29;163(1):339-51. | |||||
REF 2 | Shire Announces NDA Submission of Guanfacine Extended Release for the Treatment of ADHD in Children and Adolescents, 2009. FDA Approved - September 2, 2009 | |||||
REF 3 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
REF 4 | 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 5 | 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 6 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014166) | |||||
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 800007941) | |||||
REF 9 | 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 10 | 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 11 | 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 12 | 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 13 | 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 14 | Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges. Cardiovasc Hematol Agents Med Chem. 2009 October; 7(4): 260-269. | |||||
REF 15 | 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 16 | S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine. J Pharmacol Exp Ther. 2000 Dec;295(3):1206-22. | |||||
REF 17 | 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 18 | Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8. | |||||
REF 19 | alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs. J Med Chem. 1982 Dec;25(12):1389-401. | |||||
REF 20 | Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. | |||||
REF 21 | 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 22 | Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists. J Med Chem. 1997 Jan 3;40(1):18-23. | |||||
REF 23 | 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 24 | 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 25 | Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines. J Med Chem. 1984 Sep;27(9):1182-5. | |||||
REF 26 | 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 27 | 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 28 | 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 29 | 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 30 | 1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity. J Med Chem. 2006 Jan 12;49(1):318-28. | |||||
REF 31 | 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 32 | 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 33 | Exploring the active site of phenylethanolamine N-methyltransferase with 3-hydroxyethyl- and 3-hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoqui... Bioorg Med Chem Lett. 2005 Feb 15;15(4):1143-7. | |||||
REF 34 | 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 35 | 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 36 | Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affini... J Med Chem. 2000 Apr 6;43(7):1423-6. | |||||
REF 37 | Binding of an imidazopyridoindole at imidazoline I2 receptors. Bioorg Med Chem Lett. 2004 Jan 19;14(2):527-9. | |||||
REF 38 | Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem. 1995 Sep 15;38(19):3681-716. | |||||
REF 39 | Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1. Bioorg Med Chem Lett. 2005 Sep 1;15(17):3853-6. | |||||
REF 40 | Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Aug;24(6):955-77. | |||||
REF 41 | Potent alpha(2A)-adrenoceptor-mediated vasoconstriction by brimonidine in porcine ciliary arteries. Invest Ophthalmol Vis Sci. 2001 Aug;42(9):2049-55. | |||||
REF 42 | Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1075-83. | |||||
REF 43 | Selective irreversible binding of chloroethylclonidine at alpha 1- and alpha 2-adrenoceptor subtypes. Mol Pharmacol. 1993 Dec;44(6):1165-70. | |||||
REF 44 | The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20. | |||||
REF 45 | 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 46 | 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors. J Med Chem. 1986 Aug;29(8):1394-8. | |||||
REF 47 | 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 48 | 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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