Target Information

Target General Information

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Target ID

T63967

Target Name

Neuronal acetylcholine receptor alpha-4/beta-2 (CHRNA4/B2)

Synonyms

CHRN; nAChR

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Gene Name

CHRNA4-CHRNB2

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Corneal disease [ICD-11: 9A76-9A78]

Nicotine use disorder [ICD-11: 6C4A]

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.

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BioChemical Class

Neurotransmitter receptor

UniProt ID

ACHA4_HUMAN ; ACHB2_HUMAN

Sequence

MELGGPGAPRLLPPLLLLLGTGLLRASSHVETRAHAEERLLKKLFSGYNKWSRPVANISD
VVLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWR
PDIVLYNNADGDFAVTHLTKAHLFHDGRVQWTPPAIYKSSCSIDVTFFPFDQQNCTMKFG
SWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIR
RLPLFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTS
LVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPRTHTMPTWVRRVFLDIVPRLLLMKR
PSVVKDNCRRLIESMHKMASAPRFWPEPEGEPPATSGTQSLHPPSPSFCVPLDVPAEPGP
SCKSPSDQLPPQQPLEAEKASPHPSPGPCRPPHGTQAPGLAKARSLSVQHMSSPGEAVEG
GVRCRSRSIQYCVPRDDAAPEADGQAAGALASRNTHSAELPPPDQPSPCKCTCKKEPSSV
SPSATVKTRSTKAPPPHLPLSPALTRAVEGVQYIADHLKAEDTDFSVKEDWKYVAMVIDR
IFLWMFIIVCLLGTVGLFLPPWLAGMI

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Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Varenicline

Drug Info

Approved

Smoking dependence

[1], [3]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

AZD-1446

Drug Info

Phase 2

Alzheimer disease

[4]

CP-601927

Drug Info

Phase 2

Gastrointestinal disease

[5]

Sofinicline

Drug Info

Phase 2

Attention deficit hyperactivity disorder

[6]

TC-6499-12

Drug Info

Phase 2

Irritable bowel syndrome

[7]

TC-2216

Drug Info

Phase 1

Mood disorder

[9]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

Dianicline

Drug Info

Discontinued in Phase 3

Tobacco dependence

[10]

ABT-089

Drug Info

Discontinued in Phase 2

Dementia

[11]

Ispronicline

Drug Info

Discontinued in Phase 2

Alzheimer disease

[12]

TC-2696

Drug Info

Discontinued in Phase 2

Pain

[13]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

A-366833

Drug Info

Preclinical

Pain

[14]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 11 Modulator drugs

Varenicline

Drug Info

[1]

AZD-1446

Drug Info

[17]

CP-601927

Drug Info

[18]

Sofinicline

Drug Info

[6]

TC-6499-12

Drug Info

[19]

TC-2216

Drug Info

[20]

Dianicline

Drug Info

[21]

ABT-089

Drug Info

[22]

Ispronicline

Drug Info

[23]

TC-2696

Drug Info

[24]

A-366833

Drug Info

[25]

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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

References

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REF 1

2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.

REF 2

Drug information of Metocurine Iodide, 2008. eduDrugs.

REF 3

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: 5459).

REF 4

ClinicalTrials.gov (NCT01012375) Study to Investigate the Efficacy and Tolerability of AZD1446 in Adult ADHD Patients.. U.S. National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT01098240) A Study Of The Efficacy And Safety Of CP-601,927 Augmentation Of Antidepressant Therapy In Major Depression. U.S. National Institutes of Health.

REF 6

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.

REF 7

ClinicalTrials.gov (NCT01149200) Proof-of-Principle Study of TC-6499 in the Treatment of Constipation Predominant Irritable Bowel Syndrome (IBS). U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT03551288) Effect of Food, Gender, and Age on the Pharmacokinetic Profile of SUVN-911 in Healthy Subjects (SUVN-911). U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT00583544) A Safety and Tolerability Single Ascending Dose Study in Healthy Volunteers. U.S. National Institutes of Health.

REF 10

Emerging drugs for the treatment of tobacco dependence. Expert Opin Emerg Drugs. 2009 Mar;14(1):23-32.

REF 11

Emerging drugs for attention-deficit/hyperactivity disorder. Expert Opin Emerg Drugs. 2007 Sep;12(3):423-34.

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011083)

REF 13

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021012)

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020139)

REF 15

Pharmacological characterization of (S)-(2)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine HCl (SIB-1508Y, Altinicline), a novel nicotinic acetylcholine receptor agonist. Brain Res. 2008 Oct 9;1234:16-24.

REF 16

Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist. Pharm Acta Helv. 2000 Mar;74(2-3):125-30.

REF 17

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.

REF 18

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.

REF 19

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 20

TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity.CNS Neurosci Ther.2008 Winter;14(4):266-77.

REF 21

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.

REF 22

Selectivity of ABT-089 for alpha4beta2* and alpha6beta2* nicotinic acetylcholine receptors in brain.Biochem Pharmacol.2009 Oct 1;78(7):795-802.

REF 23

Ispronicline: a novel alpha4beta2 nicotinic acetylcholine receptor-selective agonist with cognition-enhancing and neuroprotective properties. J Mol Neurosci. 2006;30(1-2):19-20.

REF 24

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.

REF 25

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.

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