Target Information

Target General Information

Target ID

T11448 (Former ID: TTDS00032)

Target Name

Adrenergic receptor alpha-2A (ADRA2A)

Synonyms

Alpha-2AAR; Alpha-2A adrenoreceptor; Alpha-2A adrenoceptor; Alpha-2A adrenergic receptor; Alpha-2 adrenergic receptor subtype C10; ADRAR; ADRA2R

Gene Name

ADRA2A

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Attention deficit hyperactivity disorder [ICD-11: 6A05]

Opioid use disorder [ICD-11: 6C43]

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

UniProt ID

ADA2A_HUMAN

Sequence

MFRQEQPLAEGSFAPMGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLML
LTVFGNVLVIIAVFTSRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAW
CEIYLALDVLFCTSSIVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVIS
FPPLISIEKKGGGGGPQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKR
RTRVPPSRRGPDAVAAPPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGP
RDTDALDLEESSSSDHAERPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTP
AAGPGEERVGAAKASRWRGRQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPR
TLFKFFFWFGYCNSSLNPVIYTIFNHDFRRAFKKILCRGDRKRIV

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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

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Approved Drug(s)

[+] 3 Approved Drugs

Connexyn

Drug Info

Approved

Attention deficit hyperactivity disorder

[2]

Lofexidine

Drug Info

Approved

Opioid dependence

[3]

MOXONIDINE

Drug Info

Approved

Alcohol dependence

[4]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

MEDETOMIDINE

Drug Info

Phase 2

Pain

[5]

DSP-1200

Drug Info

Phase 1

Depression

[6]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

NMI-870

Drug Info

Discontinued in Phase 2

Sexual dysfunction

[7]

S-18616

Drug Info

Terminated

Pain

[8]

SNAP-5089

Drug Info

Terminated

Heart arrhythmia

[9], [10]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 4 Agonist drugs

Connexyn

Drug Info

[1]

Lofexidine

Drug Info

[3]

Beta-methoxyamphetamine

Drug Info

[40]

Chloroethylclonidine

Drug Info

[43]

Inhibitor

[+] 70 Inhibitor drugs

MOXONIDINE

Drug Info

[11]

MEDETOMIDINE

Drug Info

[12]

MAZAPERTINE

Drug Info

[13]

A-80426

Drug Info

[15]

SK&F-104078

Drug Info

[17]

SNAP-5089

Drug Info

[18]

WB-4101

Drug Info

[19]

(+/-)-nantenine

Drug Info

[20]

(1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol

Drug Info

[21]

(1H-Benzoimidazol-5-yl)-(1H-imidazol-2-yl)-amine

Drug Info

[22]

(1H-Imidazol-2-yl)-quinoxalin-6-yl-amine

Drug Info

[22]

(2,6-Dichloro-phenyl)-(1H-imidazol-2-yl)-amine

Drug Info

[22]

(2-Bromo-phenyl)-(1H-imidazol-2-yl)-amine

Drug Info

[22]

(2-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine

Drug Info

[23]

(3-Ethyl-indol-1-yl)-propyl-pyridin-4-yl-amine

Drug Info

[23]

(3-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine

Drug Info

[23]

(R)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[24]

(S)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[24]

1',2',3',6'-Tetrahydro-[2,4']bipyridinyl

Drug Info

[25]

1,2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline

Drug Info

[26]

1,2,3,4,5,6-Hexahydro-benzo[c]azocine

Drug Info

[24]

1,2,3,4-Tetrahydro-benzo[h]isoquinolin-8-ol

Drug Info

[27]

1,2,3,4-Tetrahydro-isoquinolin-7-ol

Drug Info

[27]

1,2,3,4-Tetrahydro-pyrazino[1,2-a]indole

Drug Info

[28]

1,2,3,4-tetrahydroisoquinoline

Drug Info

[29]

1-((S)-2-aminopropyl)-1H-indazol-6-ol

Drug Info

[30]

1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazine

Drug Info

[25]

1-(pyridin-2-yl)piperazine

Drug Info

[25]

2,3,4,5-Tetrahydro-1H-benzo[c]azepine

Drug Info

[24]

2,3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine

Drug Info

[24]

2,3,4,5-Tetrahydro-benzo[f][1,4]oxazepine

Drug Info

[24]

2,3-Dihydro-1H-isoindole

Drug Info

[24]

2-BFi

Drug Info

[31]

3-Fluoromethyl-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[32]

3-Methoxymethyl-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[21]

3-Methyl-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[24]

3-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[33]

4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole

Drug Info

[12]

4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one

Drug Info

[34]

4-(4-Methyl-indan-1-yl)-1H-imidazole

Drug Info

[35]

4-Benzo[b]thiophen-4-yl-1H-imidazole

Drug Info

[36]

5-Aminomethyl-naphthalen-2-ol

Drug Info

[27]

6,7,8,9-Tetrahydro-5-thia-8-aza-benzocycloheptene

Drug Info

[24]

7-Methoxy-2,3,4,9-tetrahydro-1H-beta-carboline

Drug Info

[37]

7-Nitro-1,2,3,4-tetrahydro-isoquinoline

Drug Info

[33]

8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline

Drug Info

[27]

AKUAMMIGINE

Drug Info

[38]

AR-129330

Drug Info

[39]

Butyl-indol-1-yl-pyridin-4-yl-amine

Drug Info

[23]

C-(6-Methoxy-naphthalen-1-yl)-methylamine

Drug Info

[27]

C-Naphthalen-1-yl-methylamine

Drug Info

[27]

Ethyl-indol-1-yl-pyridin-4-yl-amine

Drug Info

[23]

GNF-PF-2857

Drug Info

[45]

GNF-PF-3878

Drug Info

[45]

Indol-1-yl-methyl-pyridin-4-yl-amine

Drug Info

[23]

Indol-1-yl-prop-2-ynyl-pyridin-4-yl-amine

Drug Info

[23]

Indol-1-yl-pyridin-4-yl-amine

Drug Info

[23]

JP1302

Drug Info

[45]

METHYLNORADRENALINE

Drug Info

[19]

MEZILAMINE

Drug Info

[46]

PIPEROXAN

Drug Info

[19]

R-226161

Drug Info

[47]

S-34324

Drug Info

[15]

SK&F-29661

Drug Info

[33]

SK&F-64139

Drug Info

[29]

SNAP-5150

Drug Info

[18]

TRACIZOLINE

Drug Info

[37]

Tramazoline

Drug Info

[19]

TRYPTOLINE

Drug Info

[37]

[3H]RX821002

Drug Info

[48]

Antagonist

[+] 3 Antagonist drugs

DSP-1200

Drug Info

[6]

BRL 44408

Drug Info

[41], [42]

Ciproxifan

Drug Info

[44]

Modulator

[+] 2 Modulator drugs

NMI-870

Drug Info

[14]

S-18616

Drug Info

[16]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

cGMP-PKG signaling pathway

Neuroactive ligand-receptor interaction

Panther Pathway

[+] 1 Panther Pathways

Alpha adrenergic receptor signaling pathway

Reactome

[+] 6 Reactome Pathways

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

[+] 6 WikiPathways

Monoamine GPCRs

GPCRs, Class A Rhodopsin-like

Platelet Aggregation (Plug Formation)

Integration of energy metabolism

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

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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