Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWG9A4)

• DTT 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
• DTT Type: Successful target; [1]
• Related Disease:
  Attention deficit hyperactivity disorder [ICD-11: 6A05]
  Opioid use disorder [ICD-11: 6C43]
  Substance abuse [ICD-11: 6C40]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: ADA2A_HUMAN
• TTD ID: T11448
• Sequence:
  MFRQEQPLAEGSFAPMGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLML
  LTVFGNVLVIIAVFTSRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAW
  CEIYLALDVLFCTSSIVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVIS
  FPPLISIEKKGGGGGPQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKR
  RTRVPPSRRGPDAVAAPPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGP
  RDTDALDLEESSSSDHAERPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTP
  AAGPGEERVGAAKASRWRGRQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPR
  TLFKFFFWFGYCNSSLNPVIYTIFNHDFRRAFKKILCRGDRKRIV
• 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.
• Reactome Pathway:
  Adrenaline signalling through Alpha-2 adrenergic receptor (R-HSA-392023)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Surfactant metabolism (R-HSA-5683826)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Connexyn	DMF29Q5	Attention deficit hyperactivity disorder	6A05.Z	Approved	[1]
Lofexidine	DM1WXA6	Heroin and opiate withdrawal	6C43	Approved	[2]
MOXONIDINE	DMGFB0E	Alcohol dependence	6C40.2	Approved	[3]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MEDETOMIDINE	DMX9Y7V	Pain	MG30-MG3Z	Phase 2	[4]
DSP-1200	DM4WSHG	Depression	6A70-6A7Z	Phase 1	[5]

7 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MAZAPERTINE	DMRHYAU	N. A.	N. A.	Discontinued in Phase 2	[6]
NMI-870	DMU596F	Sexual dysfunction	HA00-HA01	Discontinued in Phase 2	[7]
A-80426	DMBC3DG	N. A.	N. A.	Terminated	[8]
S-18616	DMQ8S4L	Pain	MG30-MG3Z	Terminated	[9]
SK&F-104078	DMRADBU	N. A.	N. A.	Terminated	[10]
SNAP-5089	DMROJEN	Heart arrhythmia	BC65	Terminated	[11]
WB-4101	DMQU8B1	N. A.	N. A.	Terminated	[12]

67 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-nantenine	DM0L3GE	Discovery agent	N.A.	Investigative	[13]
(1,2,3,4-Tetrahydro-isoquinolin-3-yl)-methanol	DMF6WHC	Discovery agent	N.A.	Investigative	[14]
(1H-Benzoimidazol-5-yl)-(1H-imidazol-2-yl)-amine	DMPKM9B	Discovery agent	N.A.	Investigative	[15]
(1H-Imidazol-2-yl)-quinoxalin-6-yl-amine	DMRDHL2	Discovery agent	N.A.	Investigative	[15]
(2,6-Dichloro-phenyl)-(1H-imidazol-2-yl)-amine	DM27TH9	Discovery agent	N.A.	Investigative	[15]
(2-Bromo-phenyl)-(1H-imidazol-2-yl)-amine	DM8N79M	Discovery agent	N.A.	Investigative	[15]
(2-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine	DME6MYZ	Discovery agent	N.A.	Investigative	[16]
(3-Ethyl-indol-1-yl)-propyl-pyridin-4-yl-amine	DM5WJBH	Discovery agent	N.A.	Investigative	[16]
(3-Methyl-indol-1-yl)-propyl-pyridin-4-yl-amine	DMHED9G	Discovery agent	N.A.	Investigative	[16]
(R)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline	DM98L2X	Discovery agent	N.A.	Investigative	[17]
(S)-3-Methyl-1,2,3,4-tetrahydro-isoquinoline	DMS4JAG	Discovery agent	N.A.	Investigative	[17]
1',2',3',6'-Tetrahydro-[2,4']bipyridinyl	DMFDK4N	Discovery agent	N.A.	Investigative	[18]
1,2,3,4,4a,5,10,10a-Octahydro-benzo[g]quinoline	DMDYX7P	Discovery agent	N.A.	Investigative	[19]
1,2,3,4,5,6-Hexahydro-benzo[c]azocine	DMTKYFE	Discovery agent	N.A.	Investigative	[17]
1,2,3,4-Tetrahydro-benzo[h]isoquinolin-8-ol	DMHKANE	Discovery agent	N.A.	Investigative	[20]
1,2,3,4-Tetrahydro-isoquinolin-7-ol	DM5VLIE	Discovery agent	N.A.	Investigative	[20]
1,2,3,4-Tetrahydro-pyrazino[1,2-a]indole	DM3JGVF	Discovery agent	N.A.	Investigative	[21]
1,2,3,4-tetrahydroisoquinoline	DMZGCEQ	Discovery agent	N.A.	Investigative	[22]
1-((S)-2-aminopropyl)-1H-indazol-6-ol	DMU83KP	Discovery agent	N.A.	Investigative	[23]
1-(3-Fluoro-pyridin-2-yl)-4-methyl-piperazine	DMWFU3T	Discovery agent	N.A.	Investigative	[18]
1-(pyridin-2-yl)piperazine	DMKE7FG	Discovery agent	N.A.	Investigative	[18]
2,3,4,5-Tetrahydro-1H-benzo[c]azepine	DM1RE9Q	Discovery agent	N.A.	Investigative	[17]
2,3,4,5-Tetrahydro-1H-benzo[e][1,4]diazepine	DM4EZOB	Discovery agent	N.A.	Investigative	[17]
2,3,4,5-Tetrahydro-benzo[f][1,4]oxazepine	DMOFG4M	Discovery agent	N.A.	Investigative	[17]
2,3-Dihydro-1H-isoindole	DMWI9XS	Discovery agent	N.A.	Investigative	[17]
2-BFi	DMFAW4R	Discovery agent	N.A.	Investigative	[24]
3-Fluoromethyl-1,2,3,4-tetrahydro-isoquinoline	DMDPUC7	Discovery agent	N.A.	Investigative	[25]
3-Methoxymethyl-1,2,3,4-tetrahydro-isoquinoline	DMH1RX6	Discovery agent	N.A.	Investigative	[14]
3-Methyl-1,2,3,4-tetrahydro-isoquinoline	DMIWQ7G	Discovery agent	N.A.	Investigative	[17]
3-Methyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline	DMZY6VX	Discovery agent	N.A.	Investigative	[26]
4-(1-Naphthalen-1-yl-ethyl)-1H-imidazole	DMFYBLH	Discovery agent	N.A.	Investigative	[4]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[27]
4-(4-Methyl-indan-1-yl)-1H-imidazole	DMYZHXR	Discovery agent	N.A.	Investigative	[28]
4-Benzo[b]thiophen-4-yl-1H-imidazole	DM02Q8N	Discovery agent	N.A.	Investigative	[29]
5-Aminomethyl-naphthalen-2-ol	DMTP9DB	Discovery agent	N.A.	Investigative	[20]
6,7,8,9-Tetrahydro-5-thia-8-aza-benzocycloheptene	DMNOI7B	Discovery agent	N.A.	Investigative	[17]
7-Methoxy-2,3,4,9-tetrahydro-1H-beta-carboline	DMQ1BE8	Discovery agent	N.A.	Investigative	[30]
7-Nitro-1,2,3,4-tetrahydro-isoquinoline	DMX3UV1	Discovery agent	N.A.	Investigative	[26]
8-Methoxy-1,2,3,4-tetrahydro-benzo[h]isoquinoline	DMY50UR	Discovery agent	N.A.	Investigative	[20]
AKUAMMIGINE	DMJW4I5	Discovery agent	N.A.	Investigative	[31]
AR-129330	DMUSYKG	Discovery agent	N.A.	Investigative	[32]
Beta-methoxyamphetamine	DMA9CSG	Discovery agent	N.A.	Investigative	[33]
BRL 44408	DM3WPO4	Discovery agent	N.A.	Investigative	[34], [35]
Butyl-indol-1-yl-pyridin-4-yl-amine	DM1CX9Y	Discovery agent	N.A.	Investigative	[16]
C-(6-Methoxy-naphthalen-1-yl)-methylamine	DMJ6SYI	Discovery agent	N.A.	Investigative	[20]
C-Naphthalen-1-yl-methylamine	DMFW1JC	Discovery agent	N.A.	Investigative	[20]
Chloroethylclonidine	DMKZIES	Discovery agent	N.A.	Investigative	[36]
Ciproxifan	DM9N8WM	Dementia	6D80-6D86	Investigative	[37]
Ethyl-indol-1-yl-pyridin-4-yl-amine	DM3CWFR	Discovery agent	N.A.	Investigative	[16]
GNF-PF-2857	DML5QFZ	Discovery agent	N.A.	Investigative	[38]
GNF-PF-3878	DM7BXHQ	Discovery agent	N.A.	Investigative	[38]
Indol-1-yl-methyl-pyridin-4-yl-amine	DMJB876	Discovery agent	N.A.	Investigative	[16]
Indol-1-yl-prop-2-ynyl-pyridin-4-yl-amine	DMR9GNW	Discovery agent	N.A.	Investigative	[16]
Indol-1-yl-pyridin-4-yl-amine	DM1F53L	Discovery agent	N.A.	Investigative	[16]
JP1302	DMMVBK6	Discovery agent	N.A.	Investigative	[38]
METHYLNORADRENALINE	DMOWMPL	Discovery agent	N.A.	Investigative	[12]
MEZILAMINE	DMVYWJS	Discovery agent	N.A.	Investigative	[39]
PIPEROXAN	DMIHO0P	Discovery agent	N.A.	Investigative	[12]
R-226161	DM4BP7S	Discovery agent	N.A.	Investigative	[40]
S-34324	DMZLQ5W	Discovery agent	N.A.	Investigative	[8]
SK&F-29661	DM2KFQ5	Discovery agent	N.A.	Investigative	[26]
SK&F-64139	DM60Y3Q	Discovery agent	N.A.	Investigative	[22]
SNAP-5150	DM2OLGQ	Discovery agent	N.A.	Investigative	[11]
TRACIZOLINE	DM18CV3	Discovery agent	N.A.	Investigative	[30]
Tramazoline	DM3ML0N	Discovery agent	N.A.	Investigative	[12]
TRYPTOLINE	DMV19K7	Discovery agent	N.A.	Investigative	[30]
[3H]RX821002	DM6IRN4	Discovery agent	N.A.	Investigative	[41]

References

• [1] alpha2A-adrenergic receptors heterosynaptically regulate glutamatergic transmission in the bed nucleus of the stria terminalis. Neuroscience. 2009 Sep 29;163(1):339-51.
• [2] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [3] 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.
• [4] 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.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 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.
• [7] Female Sexual Dysfunction: Therapeutic Options and Experimental Challenges. Cardiovasc Hematol Agents Med Chem. 2009 October; 7(4): 260-269.
• [8] 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.
• [9] 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.
• [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.
• [11] Design and synthesis of novel dihydropyridine alpha-1a antagonists. Bioorg Med Chem Lett. 1999 Oct 4;9(19):2843-8.
• [12] alpha 2 adrenoceptors: classification, localization, mechanisms, and targets for drugs. J Med Chem. 1982 Dec;25(12):1389-401.
• [13] Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.
• [14] 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.
• [15] Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists. J Med Chem. 1997 Jan 3;40(1):18-23.
• [16] 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.
• [17] 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.
• [18] Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines. J Med Chem. 1984 Sep;27(9):1182-5.
• [19] N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies. J Med Chem. 1998 Oct 8;41(21):4165-70.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [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.
• [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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Binding of an imidazopyridoindole at imidazoline I2 receptors. Bioorg Med Chem Lett. 2004 Jan 19;14(2):527-9.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] Potent alpha(2A)-adrenoceptor-mediated vasoconstriction by brimonidine in porcine ciliary arteries. Invest Ophthalmol Vis Sci. 2001 Aug;42(9):2049-55.
• [35] Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol. 2000 Apr;278(4):H1075-83.
• [36] Selective irreversible binding of chloroethylclonidine at alpha 1- and alpha 2-adrenoceptor subtypes. Mol Pharmacol. 1993 Dec;44(6):1165-70.
• [37] The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20.
• [38] Structure-activity relationship of quinoline derivatives as potent and selective alpha(2C)-adrenoceptor antagonists. J Med Chem. 2006 Oct 19;49(21):6351-63.
• [39] 4-Amino-6-chloro-2-piperazinopyrimidines with selective affinity for alpha 2-adrenoceptors. J Med Chem. 1986 Aug;29(8):1394-8.
• [40] 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.
• [41] Alpha-adrenoreceptor reagents. 4. Resolution of some potent selective prejunctional alpha 2-adrenoreceptor antagonists. J Med Chem. 1986 Oct;29(10):2000-3.