Target Information

Target General Infomation
Target ID
T11448
Former ID
TTDS00032
Target Name
Alpha-2A adrenergic receptor
Gene Name
ADRA2A
Synonyms
Alpha-2A adrenoceptor; Alpha-2A adrenoreceptor; Alpha-2AAR subtype C10; ADRA2A
Target Type
Successful
Disease Attention deficit hyperactivity disorder [ICD9: 314; ICD10: F90]
Alcohol use disorders [ICD9: 303; ICD10: F10.2]
Dementia; Obesity [ICD9:290-294, 278; ICD10: F01-F07, E66]
Heart arrhythmia [ICD10: I47-I49]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Sexual dysfunction [ICD9: 302.7; ICD10: F52]
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 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.
BioChemical Class
GPCR rhodopsin
Target Validation
T11448
UniProt ID
P08913
Sequence
MGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLMLLTVFGNVLVIIAVFT
SRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAWCEIYLALDVLFCTSS
IVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVISFPPLISIEKKGGGGG
PQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKRRTRVPPSRRGPDAVA
APPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGPRDTDALDLEESSSSD
HAERPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTPAAGPGEERVGAAKAS
RWRGRQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPRTLFKFFFWFGYCNSS
LNPVIYTIFNHDFRRAFKKILCRGDRKRIV
Drugs and Mode of Action
Drug(s) Connexyn Drug Info Approved Attention deficit hyperactivity disorder [550610]
MOXONIDINE Drug Info Approved Alcohol use disorders [526626]
MEDETOMIDINE Drug Info Phase 2 Pain [529347]
MAZAPERTINE Drug Info Discontinued in Phase 2 Discovery agent [545274]
NMI-870 Drug Info Discontinued in Phase 2 Sexual dysfunction [547220]
A-80426 Drug Info Terminated Discovery agent [546043]
S-18616 Drug Info Terminated Pain [546405]
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]
(1H-Benzoimidazol-5-yl)-(1H-imidazol-2-yl)-amine Drug Info [534315]
(1H-Imidazol-2-yl)-quinoxalin-6-yl-amine Drug Info [534315]
(2,6-Dichloro-phenyl)-(1H-imidazol-2-yl)-amine Drug Info [534315]
(2-Bromo-phenyl)-(1H-imidazol-2-yl)-amine Drug Info [534315]
(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-((S)-2-aminopropyl)-1H-indazol-6-ol Drug Info [527952]
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]
3-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline Drug Info [527414]
4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole Drug Info [533805]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [531079]
4-(4-Methyl-indan-1-yl)-1H-imidazole Drug Info [534467]
4-Benzo[b]thiophen-4-yl-1H-imidazole Drug Info [525740]
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]
7-Nitro-1,2,3,4-tetrahydro-isoquinoline Drug Info [527414]
8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline Drug Info [534531]
A-80426 Drug Info [527481]
AKUAMMIGINE Drug Info [533638]
AR-129330 Drug Info [527629]
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]
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-29661 Drug Info [527414]
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 4-Methoxyamphetamine Drug Info [551380]
Chloroethylclonidine Drug Info [537921]
Connexyn Drug Info [537472]
Antagonist BRL 44408 Drug Info [534977], [535225]
Ciproxifan Drug Info [536039]
Modulator NMI-870 Drug Info [544155]
S-18616 Drug Info [525915]
Pathways
KEGG Pathway cGMP-PKG signaling pathway
Neuroactive ligand-receptor interaction
PANTHER Pathway Alpha adrenergic receptor signaling pathway
Reactome Adrenoceptors
Adrenaline signalling through Alpha-2 adrenergic receptor
Adrenaline,noradrenaline inhibits insulin secretion
G alpha (i) signalling events
G alpha (z) signalling events
Surfactant metabolism
WikiPathways Monoamine GPCRs
GPCRs, Class A Rhodopsin-like
Platelet Aggregation (Plug Formation)
Integration of energy metabolism
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 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 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 546405Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007941)
Ref 547220Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014166)
Ref 550610Shire Announces NDA Submission of Guanfacine Extended Release for the Treatment of ADHD in Children and Adolescents, 2009. FDA Approved - September 2, 2009
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 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 525740J Med Chem. 2000 Apr 6;43(7):1423-6.Alpha(2) adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-imidazo)-1,3-dimethyl-6,7-dihydro-thianaphthene as a high-affinity ligand for the alpha(2D) adrenergic receptor.
Ref 525915S18616, 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 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 527414Bioorg Med Chem Lett. 2005 Feb 15;15(4):1143-7.Exploring the active site of phenylethanolamine N-methyltransferase with 3-hydroxyethyl- and 3-hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoquinolines.
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 527629Bioorg Med Chem Lett. 2005 Sep 1;15(17):3853-6.Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.
Ref 527952J Med Chem. 2006 Jan 12;49(1):318-28.1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive 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 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 531079J Med Chem. 2010 Sep 9;53(17):6386-97.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 receptor agonist with unprecedented selectivity and procognitive potential.
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 533638J Med Chem. 1995 Sep 15;38(19):3681-716.Alpha- and beta-adrenoceptors: from the gene to the clinic. 2. Structure-activity relationships and therapeutic applications.
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 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 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 534315J Med Chem. 1997 Jan 3;40(1):18-23.Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists.
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 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 534977Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1075-83.
Ref 535225Potent alpha(2A)-adrenoceptor-mediated vasoconstriction by brimonidine in porcine ciliary arteries. Invest Ophthalmol Vis Sci. 2001 Aug;42(9):2049-55.
Ref 536039The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20.
Ref 537472Alpha(2A)-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuroscience. 2009 Jun 12.
Ref 537921Selective irreversible binding of chloroethylclonidine at alpha 1- and alpha 2-adrenoceptor subtypes. Mol Pharmacol. 1993 Dec;44(6):1165-70.
Ref 544155Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges. Cardiovasc Hematol Agents Med Chem. 2009 October; 7(4): 260-269.
Ref 551380Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat. Prog Neuropsychopharmacol Biol Psychiatry. 2000 Aug;24(6):955-77.

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