Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTL1ATN)

• DTT Name: Neuronal acetylcholine receptor alpha-4/beta-2 (CHRNA4/B2)
• Synonyms: CHRN; nAChR
• Gene Name: CHRNA4-CHRNB2
• DTT Type: Successful target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: ACHA4_HUMAN ; ACHB2_HUMAN
• TTD ID: T63967
• Sequence:
  MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
  VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR
  PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG
  SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR
  RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS
  LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR
  PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP
  SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG
  GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV
  SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR
  IFLWMFIIVCLLGTVGLFLPPWLAGMI
• Function: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeable to sodiun ions.

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Metocurine Iodide	DMZJYBW	Anaesthesia	9A78.6	Approved	[2]
Varenicline	DMMUOLJ	Drug dependence		Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD-1446	DM7B1AR	Alzheimer disease	8A20	Phase 2	[3]
CP-601927	DMKJFDM	Gastrointestinal disease	DE2Z	Phase 2	[4]
Sofinicline	DM157U0	Attention deficit hyperactivity disorder	6A05.Z	Phase 2	[5]
TC-6499-12	DMWPI2U	Irritable bowel syndrome	DD91.0	Phase 2	[6]
SUVN 911	DMZP671	Major depressive disorder	6A70.3	Phase 1	[7]
TC-2216	DM4W92J	Mood disorder	6A60-6E23	Phase 1	[8]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dianicline	DMX2SHT	Tobacco dependence	6C4A.2	Discontinued in Phase 3	[9]
ABT-089	DM8DT7U	Anxiety disorder	6B00-6B0Z	Discontinued in Phase 2	[10]
Ispronicline	DMKY2UE	Alzheimer disease	8A20	Discontinued in Phase 2	[11]
TC-2696	DMP1A4S	Pain	MG30-MG3Z	Discontinued in Phase 2	[12]
SIB-1508Y	DMT43AI	Parkinson disease	8A00.0	Terminated	[14]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
A-366833	DML5SO1	Pain	MG30-MG3Z	Preclinical	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	3.51E-10	-0.15	-0.61
Irritable bowel syndrome	DD91.0	Rectal colon tissue	1.09E-01	-3.94E-03	-0.02
Parkinson's disease	8A00.0	Substantia nigra tissue	1.04E-01	-0.12	-0.71
Schizophrenia	6A20	Pre-frontal cortex	7.65E-01	0.02	0.15
Schizophrenia	6A20	Superior temporal cortex	9.89E-01	-0.01	-0.11

References

• [1] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [2] NMR study of general anesthetic interaction with nAChR beta2 subunit.Biophys J.2008 Mar 1;94(5):1681-8.
• [3] A randomized, double-blind, placebo-controlled crossover study of 4 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder.Psychopharmacology (Berl). 2014 Mar;231(6):1251-65.
• [4] Toxicity study in juvenile rats with the alpha4beta2 nicotinic acetylcholine receptor partial agonist CP-601,927. Birth Defects Res B Dev Reprod Toxicol. 2011 Aug;92(4):323-32.
• [5] Sofinicline: a novel nicotinic acetylcholine receptor agonist in the treatment of attention-deficit/hyperactivity disorder. Expert Opin Investig Drugs. 2014 Aug;23(8):1157-63.
• [6] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [7] Discovery and Development of 3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane Hydrochloride (SUVN-911): A Novel, Potent, Selective, and Orally Active Neuronal Nicotinic Acetylcholine alpha42 Receptor Antagonist for the Treatment of Depression. J Med Chem. 2020 Mar 26;63(6):2833-2853.
• [8] TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity.CNS Neurosci Ther.2008 Winter;14(4):266-77.
• [9] Dianicline, a novel 42 nicotinic acetylcholine receptor partial agonist, for smoking cessation: a randomized placebo-controlled clinical trial.Nicotine Tob Res.2011 Jan;13(1):1-6.
• [10] Selectivity of ABT-089 for alpha4beta2* and alpha6beta2* nicotinic acetylcholine receptors in brain.Biochem Pharmacol.2009 Oct 1;78(7):795-802.
• [11] Ispronicline: a novel alpha4beta2 nicotinic acetylcholine receptor-selective agonist with cognition-enhancing and neuroprotective properties. J Mol Neurosci. 2006;30(1-2):19-20.
• [12] alpha4beta2 Nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats. Neuropharmacology. 2013 Aug;71:191-203.
• [13] Antinociceptive activity of alpha4beta2* neuronal nicotinic receptor agonist A-366833 in experimental models of neuropathic and inflammatory pain. Eur J Pharmacol. 2011 Oct 1;668(1-2):155-62.
• [14] Nicotinic Receptors in Neurodegeneration