Target Information

Target General Information

Target ID

T34429 (Former ID: TTDS00520)

Target Name

Neuronal acetylcholine receptor alpha-7 (CHRNA7)

Synonyms

Nicotinic acetylcholine receptor subunit alpha 7; Nicotinic acetylcholine receptor alpha7; CHRNA7; Alpha7 nicotinic receptor; Alpha7 nAChR; Alpha-7 nAChR; Alpha(7) nicotinic receptor

Gene Name

CHRNA7

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

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

Schizophrenia [ICD-11: 6A20]

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. The channel is blocked by alpha-bungarotoxin.

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BioChemical Class

Neurotransmitter receptor

UniProt ID

ACHA7_HUMAN

Sequence

MRCSPGGVWLALAASLLHVSLQGEFQRKLYKELVKNYNPLERPVANDSQPLTVYFSLSLL
QIMDVDEKNQVLTTNIWLQMSWTDHYLQWNVSEYPGVKTVRFPDGQIWKPDILLYNSADE
RFDATFHTNVLVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQHCKLKFGSWSYGGWSLDL
QMQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIP
CVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFAST
MIIVGLSVVVTVIVLQYHHHDPDGGKMPKWTRVILLNWCAWFLRMKRPGEDKVRPACQHK
QRRCSLASVEMSAVAPPPASNGNLLYIGFRGLDGVHCVPTPDSGVVCGRMACSPTHDEHL
LHGGQPPEGDPDLAKILEEVRYIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTI
ICTIGILMSAPNFVEAVSKDFA

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3D Structure

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AlphaFold

HIT2.0 ID

T34I45

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

ALCURONIUM

Drug Info

Approved

Anaesthesia

[2], [3]

Ziprasidone

Drug Info

Approved

Schizophrenia

[1], [4], [5]

Clinical Trial Drug(s)

[+] 13 Clinical Trial Drugs

AMG 386

Drug Info

Phase 3

Neuropathic pain

[6]

CYTISINE

Drug Info

Phase 3

Tobacco dependence

[7]

EVP-6124

Drug Info

Phase 3

Schizophrenia

[8]

ABT-126

Drug Info

Phase 2

Schizophrenia

[9]

AQW-051

Drug Info

Phase 2

Alzheimer disease

[10], [11]

GTS-21

Drug Info

Phase 2

Parkinson disease

[12]

JNJ-39393406

Drug Info

Phase 2

Depression

[7]

MEM-3454

Drug Info

Phase 2

Schizophrenia

[1]

TC-6987

Drug Info

Phase 2

Asthma

[13]

AVL-3288

Drug Info

Phase 1

Cognitive impairment

[14]

BMS-933043

Drug Info

Phase 1

Psychiatric disorder

[15]

BNC375

Drug Info

Phase 1

Cognitive impairment

[16], [17]

R4996

Drug Info

Phase 1

Neurological disorder

[18]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

AZD-9684

Drug Info

Discontinued in Phase 2

Thrombosis

[19]

AZD0328

Drug Info

Discontinued in Phase 2

Alzheimer disease

[20], [21]

ABT-107

Drug Info

Discontinued in Phase 1

Attention deficit hyperactivity disorder

[22]

PNU-282987

Drug Info

Terminated

Schizophrenia

[24], [1]

Preclinical Drug(s)

[+] 2 Preclinical Drugs

PHA-568487

Drug Info

Preclinical

Cognitive impairment

[23]

RMG-40083

Drug Info

Preclinical

Schizophrenia

[1]

Mode of Action

[+] 6 Modes of Action

Inhibitor

[+] 9 Inhibitor drugs

ALCURONIUM

Drug Info

[25]

CYTISINE

Drug Info

[27]

3,8-dibromoboldine

Drug Info

[41]

3-bromoboldine

Drug Info

[41]

CP-810123

Drug Info

[47]

GCCSHPACAGNNQHIC*

Drug Info

[48]

GCCSNPVCHLEHSNLC*

Drug Info

[48]

PH-709829

Drug Info

[51]

TOXIFERINE

Drug Info

[25]

Binder

[+] 1 Binder drugs

Ziprasidone

Drug Info

[1]

Agonist

[+] 14 Agonist drugs

AMG 386

Drug Info

[26]

AQW-051

Drug Info

[30]

GTS-21

Drug Info

[31], [32]

R4996

Drug Info

[26]

PHA-568487

Drug Info

[40]

4BP-TQS

Drug Info

[42]

A-582941

Drug Info

[43]

AZD-6319

Drug Info

[45]

EVP-4473

Drug Info

[45]

JN-711

Drug Info

[45]

PSAB-OFP

Drug Info

[53]

[125I]epibatidine

Drug Info

[45]

[3H]A-585539

Drug Info

[54]

[3H]AZ11637326

Drug Info

[55]

Modulator

[+] 11 Modulator drugs

EVP-6124

Drug Info

[28]

ABT-126

Drug Info

[29]

JNJ-39393406

Drug Info

[33]

TC-6987

Drug Info

[34]

AVL-3288

Drug Info

[35]

BMS-933043

Drug Info

[36]

BNC375

Drug Info

[16]

AZD0328

Drug Info

[38]

ABT-107

Drug Info

[39]

JNJ-1930942

Drug Info

[45]

PheTQS

Drug Info

[45]

Antagonist

[+] 6 Antagonist drugs

MEM-3454

Drug Info

[1]

AZD-9684

Drug Info

[37]

RMG-40083

Drug Info

[1]

PNU-282987

Drug Info

[1]

Barbituric acid derivative

Drug Info

[46]

[3H]methyllycaconitine

Drug Info

[45], [56], [57]

Modulator (allosteric modulator)

[+] 4 Modulator (allosteric modulator) drugs

A-867744

Drug Info

[44]

LY2087101

Drug Info

[49]

NS1738

Drug Info

[50]

PNU-120596

Drug Info

[52]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

Top

(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

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 5 KEGG Pathways

Calcium signaling pathway

Neuroactive ligand-receptor interaction

Cholinergic synapse

Nicotine addiction

Chemical carcinogenesis

Panther Pathway

[+] 2 Panther Pathways

Alzheimer disease-amyloid secretase pathway

Nicotinic acetylcholine receptor signaling pathway

Reactome

[+] 1 Reactome Pathways

Highly calcium permeable postsynaptic nicotinic acetylcholine receptors

WikiPathways

[+] 2 WikiPathways

SIDS Susceptibility Pathways

Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.

REF 2

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: 341).

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

REF 5

Emerging anxiolytics. Expert Opin Emerg Drugs. 2007 Nov;12(4):541-54.

REF 6

Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.

REF 7

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 8

ClinicalTrials.gov (NCT02004392) Study of the Safety and Clinical Effects of 2 Doses of EVP-6124 in Subjects With Alzheimer's Disease Who Complete Study EVP-6124-024 or EVP-6124-025. U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT01655680) A Study to Evaluate ABT-126 for the Treatment of Cognitive Deficits in Schizophrenia. U.S. National Institutes of Health.

REF 10

REF 11

ClinicalTrials.gov (NCT01474421) Safety and Efficacy of AQW051 in L-dopa Induced Dyskinesias in Patients With Parkinson's Disease. U.S. National Institutes of Health.

REF 12

ClinicalTrials.gov (NCT02432066) Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT01296087) TC-6987 for the Treatment of Mild to Moderate Asthma. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT01851603) Phase I Study to Evaluate the Safety and Pharmacokinetics of Oral Doses of Anvylic-3288 in Healthy Subjects. U.S. National Institutes of Health.

REF 15

ClinicalTrials.gov (NCT01605994) Multiple Ascending-Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of BMS-933043 in Healthy Subjects. U.S. National Institutes of Health.

REF 16

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 17

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 18

Clinical pipeline report, company report or official report of Roche.

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018349)

REF 20

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018503)

REF 22

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026401)

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018656)

REF 24

REF 25

Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine re... J Med Chem. 2007 Sep 20;50(19):4616-29.

REF 26

Clinical pipeline report, company report or official report of Roche (2009).

REF 27

3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4889-97.

REF 28

Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract. 2014 Jan;20(1):12-24.

REF 29

A phase 2 randomized, controlled trial of the alpha7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia. Alzheimer's & Dementia: Translational Research & Clinical Interventions Volume 1, Issue 1, June 2015, Pages 81-90.

REF 30

AQW051, a novel and selective nicotinic acetylcholine receptor alpha7 partial agonist, reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys. Parkinsonism Relat Disord. 2014 Nov;20(11):1119-23.

REF 31

The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease: studies with DMXBA (GTS-21). Behav Brain Res. 2000 Aug;113(1-2):169-81.

REF 32

Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl). 1998 Apr;136(4):320-7.

REF 33

Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. Neuropharmacology. 2013 Jan;64:197-204.

REF 34

ClinicalTrials.gov (NCT01293669) Glycemic Control, Safety and Tolerability of TC-6987 Monotherapy in Type 2 Diabetes Mellitus. U.S. National Institutes of Health.

REF 35

Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6(11):e27014.

REF 36

Clinical pipeline report, company report or official report of Phrma.org Alzheimers 2012.

REF 37

Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001 Apr;94(4):643-51.

REF 38

Ultra-low exposure to -7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in -7 receptor expression in rodents: implications for low dose clinical efficacy.Neuroscience.2011 Jul 14;186:76-87.

REF 39

In vitro pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107. J Pharmacol Exp Ther. 2010 Sep 1;334(3):863-74.

REF 40

Multiple species metabolism of PHA-568487, a selective alpha 7 nicotinic acetylcholine receptor agonist. Drug Metab Lett. 2010 Aug;4(3):162-72.

REF 41

Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72.

REF 42

Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5867-72.

REF 43

Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci. 2007 Sep 26;27(39):10578-87.

REF 44

In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methy... J Pharmacol Exp Ther. 2009 Jul;330(1):257-67.

REF 45

REF 46

Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.

REF 47

Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor ag... J Med Chem. 2010 Feb 11;53(3):1222-37.

REF 48

Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45.

REF 49

Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006 Sep;318(3):1108-17.

REF 50

An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther. 2007 Oct;323(1):294-307.

REF 51

Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor:... Bioorg Med Chem Lett. 2008 Jun 15;18(12):3611-5.

REF 52

A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J Neurosci. 2005 Apr 27;25(17):4396-405.

REF 53

PSAB-OFP, a selective alpha 7 nicotinic receptor agonist, is also a potent agonist of the 5-HT3 receptor. Eur J Pharmacol. 2002 Oct 4;452(2):137-44.

REF 54

[3H]A-585539 [(1S,4S)-2,2-dimethyl-5-(6-phenylpyridazin-3-yl)-5-aza-2-azoniabicyclo[2.2.1]heptane], a novel high-affinity alpha7 neuronal nicotinic... J Pharmacol Exp Ther. 2008 Jan;324(1):179-87.

REF 55

In vitro binding characteristics of [3H]AZ11637326, a novel alpha7-selective neuronal nicotinic receptor agonist radioligand. Eur J Pharmacol. 2010 Oct 25;645(1-3):63-9.

REF 56

Nicotine increases the expression of high affinity nerve growth factor receptors in both in vitro and in vivo. Life Sci. 2002 Feb 15;70(13):1543-54.

REF 57

Experience of Black participants in the Lung Health Study smoking cessation intervention program. Nicotine Tob Res. 2001 Nov;3(4):375-82.

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