Target Information

Target General Infomation
Target ID
T34429
Former ID
TTDS00520
Target Name
Neuronal acetylcholine receptor protein, alpha-7 chain
Gene Name
CHRNA7
Synonyms
Alpha(7) nicotinic receptor; Alpha-7 nAChR; Alpha7 nAChR; Alpha7 nicotinic receptor; Nicotinic acetylcholine receptor alpha7; Nicotinic acetylcholine receptor subunit alpha 7; CHRNA7
Target Type
Successful
Disease Alzheimer disease; Schizophrenia [ICD9: 295, 331.0; ICD10: F20, G30]
Attention deficit hyperactivity disorder [ICD9: 314; ICD10: F90]
Alzheimer disease [ICD9: 331; ICD10: G30]
Anesthesia [ICD9: 338; ICD10: R20.0]
Asthma [ICD10: J45]
Cognitive disorders [ICD9: 290-294, 294.0, 780.09, 780.9, 780.93; ICD10: F01-F07, F04, F05, R41.3]
Central nervous system disease [ICD10: G00-G99]
Mild to moderate alzheimer disease; Schizophrenia [ICD9:331, 295; ICD10: G30, F20]
Neurological disease [ICD9: 338, 338.2, 410, 782.3,780; ICD10: I21, I22, R52, R52.1-R52.2, R60.9, G89]
Parkinson's disease [ICD9: 332; ICD10: G20]
Psychiatric disorder [ICD9: 290-319; ICD10: F01-F99]
Schizophrenia [ICD9: 295; ICD10: F20]
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.
BioChemical Class
Neurotransmitter receptor
Target Validation
T34429
UniProt ID
P36544
Sequence
MRCSPGGVWLALAASLLHVSLQGEFQRKLYKELVKNYNPLERPVANDSQPLTVYFSLSLL
QIMDVDEKNQVLTTNIWLQMSWTDHYLQWNVSEYPGVKTVRFPDGQIWKPDILLYNSADE
RFDATFHTNVLVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQHCKLKFGSWSYGGWSLDL
QMQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIP
CVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFAST
MIIVGLSVVVTVIVLQYHHHDPDGGKMPKWTRVILLNWCAWFLRMKRPGEDKVRPACQHK
QRRCSLASVEMSAVAPPPASNGNLLYIGFRGLDGVHCVPTPDSGVVCGRMACSPTHDEHL
LHGGQPPEGDPDLAKILEEVRYIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTI
ICTIGILMSAPNFVEAVSKDFA
Structure
2MAW
Drugs and Mode of Action
Drug(s) ALCURONIUM Drug Info Approved Anesthesia [1], [2]
TC-5280 Drug Info Approved Schizophrenia [3]
EVP-6124 Drug Info Phase 3 Mild to moderate alzheimer disease; Schizophrenia [4]
ABT-126 Drug Info Phase 2 Mild to moderate alzheimer disease; Schizophrenia [5]
AQW-051 Drug Info Phase 2 Alzheimer disease [6], [7]
GTS-21 Drug Info Phase 2 Parkinson's disease [8]
MEM-3454 Drug Info Phase 2 Schizophrenia [3]
R3487 Drug Info Phase 2 Alzheimer disease; Schizophrenia [9]
TC-6987 Drug Info Phase 2 Asthma [10]
AVL-3288 Drug Info Phase 1 Cognitive disorders [11]
BMS-933043 Drug Info Phase 1 Psychiatric disorder [12]
JNJ-39393406 Drug Info Phase 1 Cognitive disorders [13]
R4996 Drug Info Phase 1 Neurological disease [14]
PHA-568487 Drug Info Preclinical Cognitive disorders [15]
RMG-40083 Drug Info Preclinical Schizophrenia [3]
AZD0328 Drug Info Discontinued in Phase 2 Alzheimer disease [16], [17]
ABT-107 Drug Info Discontinued in Phase 1 Attention deficit hyperactivity disorder [18]
PNU-282987 Drug Info Terminated Schizophrenia [3], [19]
Inhibitor 3,8-dibromoboldine Drug Info [20]
3-bromoboldine Drug Info [20]
ALCURONIUM Drug Info [21]
CP-810123 Drug Info [22]
CYTISINE Drug Info [23]
GCCSHPACAGNNQHIC* Drug Info [24]
GCCSNPVCHLEHSNLC* Drug Info [24]
PH-709829 Drug Info [25]
TOXIFERINE Drug Info [21]
Agonist 4BP-TQS Drug Info [26]
A-582941 Drug Info [27]
AQW-051 Drug Info [28]
AZD-6319 Drug Info [29]
EVP-4473 Drug Info [29]
GTS-21 Drug Info [30], [31]
JN-711 Drug Info [29]
PHA-568487 Drug Info [32]
PHA-709829 Drug Info [25]
PSAB-OFP Drug Info [33]
R3487 Drug Info [34]
R4996 Drug Info [34]
[3H]A-585539 Drug Info [35]
[3H]AZ11637326 Drug Info [36]
[3H]epibatidine Drug Info [29]
Modulator (allosteric modulator) A-867744 Drug Info [37]
LY2087101 Drug Info [38]
NS1738 Drug Info [39]
PNU-120596 Drug Info [40]
Modulator ABT-107 Drug Info [41]
ABT-126 Drug Info [42]
AVL-3288 Drug Info [43]
AZD0328 Drug Info
BMS-933043 Drug Info [44]
EVP-6124 Drug Info [45]
JNJ-1930942 Drug Info [29]
JNJ-39393406 Drug Info [46]
PheTQS Drug Info [29]
TC-6987 Drug Info [47]
Antagonist Barbituric acid derivative Drug Info [48]
Laudanosine Drug Info [49]
MEM-3454 Drug Info [3]
Methyllycaconitine Drug Info [50], [51]
PNU-282987 Drug Info [3]
RMG-40083 Drug Info [3]
[3H]methyllycaconitine Drug Info [29]
Binder TC-5280 Drug Info [3]
Pathways
KEGG Pathway Calcium signaling pathway
Neuroactive ligand-receptor interaction
Cholinergic synapse
Nicotine addiction
Chemical carcinogenesis
PANTHER Pathway Alzheimer disease-amyloid secretase pathway
Nicotinic acetylcholine receptor signaling pathway
Reactome Highly calcium permeable postsynaptic nicotinic acetylcholine receptors
WikiPathways SIDS Susceptibility Pathways
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
References
REF 1(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 2Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 3The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22. Epub 2007 Jul 31.
REF 4ClinicalTrials.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 5ClinicalTrials.gov (NCT01655680) A Study to Evaluate ABT-126 for the Treatment of Cognitive Deficits in Schizophrenia. U.S. National Institutes of Health.
REF 6ClinicalTrials.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 7(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: 7371).
REF 8ClinicalTrials.gov (NCT02432066) Effects of GTS-21 on Smoking Behavior and Neurocognitive Functions. U.S. National Institutes of Health.
REF 9Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov. 2009 Sep;8(9):733-50.
REF 10ClinicalTrials.gov (NCT01296087) TC-6987 for the Treatment of Mild to Moderate Asthma. U.S. National Institutes of Health.
REF 11ClinicalTrials.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 12ClinicalTrials.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 13ClinicalTrials.gov (NCT01556217) A Pharmacokinetic Study to Characterize JNJ-39393406 in the Cerebrospinal Fluid of Healthy Volunteers. U.S. National Institutes of Health.
REF 14Clinical pipeline report, company report or official report of Roche.
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018656)
REF 16(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: 7697).
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018503)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026401)
REF 19(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: 3988).
REF 20Bioorg Med Chem. 2007 May 15;15(10):3368-72. Epub 2007 Mar 13.Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers.
REF 21J Med Chem. 2007 Sep 20;50(19):4616-29. Epub 2007 Aug 28.Pharmacological characteristics and binding modes of caracurine V analogues and related compounds at the neuronal alpha7 nicotinic acetylcholine receptor.
REF 22J Med Chem. 2010 Feb 11;53(3):1222-37.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 agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models.
REF 23Bioorg Med Chem Lett. 2005 Nov 15;15(22):4889-97.3,5-Bicyclic aryl piperidines: a novel class of alpha4beta2 neuronal nicotinic receptor partial agonists for smoking cessation.
REF 24J Med Chem. 2005 Jul 28;48(15):4705-45.Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations.
REF 25Bioorg Med Chem Lett. 2008 Jun 15;18(12):3611-5. Epub 2008 May 1.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: in vitro and in vivo activity.
REF 26Agonist 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 27Broad-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 28AQW051, 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 29(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. (Target id: 468).
REF 30The 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 31Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology (Berl). 1998 Apr;136(4):320-7.
REF 32Multiple species metabolism of PHA-568487, a selective alpha 7 nicotinic acetylcholine receptor agonist. Drug Metab Lett. 2010 Aug;4(3):162-72.
REF 33PSAB-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 34Clinical pipeline report, company report or official report of Roche (2009).
REF 35[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 receptor agonist: radioligand binding characterization to rat and human brain. J Pharmacol Exp Ther. 2008 Jan;324(1):179-87. Epub 2007 Oct 24.
REF 36In 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 37J Pharmacol Exp Ther. 2009 Jul;330(1):257-67. Epub 2009 Apr 23.In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile.
REF 38Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006 Sep;318(3):1108-17. Epub 2006 May 31.
REF 39An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther. 2007 Oct;323(1):294-307. Epub 2007 Jul 11.
REF 40A 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 41In 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 42A 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 43Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6(11):e27014.
REF 44Clinical pipeline report, company report or official report of Phrma.org Alzheimers 2012.
REF 45Normalizing 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 46Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. Neuropharmacology. 2013 Jan;64:197-204.
REF 47ClinicalTrials.gov (NCT01293669) Glycemic Control, Safety and Tolerability of TC-6987 Monotherapy in Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
REF 48Whiting PJ: The <span class="caps">GABAA</span> receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
REF 49Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001 Apr;94(4):643-51.
REF 50Experience of Black participants in the Lung Health Study smoking cessation intervention program. Nicotine Tob Res. 2001 Nov;3(4):375-82.
REF 51Nicotine 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.

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