Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTLA931)

• DTT 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
• DTT Type: Successful target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: ACHA7_HUMAN
• TTD ID: T34429
• Sequence:
  MRCSPGGVWLALAASLLHVSLQGEFQRKLYKELVKNYNPLERPVANDSQPLTVYFSLSLL
  QIMDVDEKNQVLTTNIWLQMSWTDHYLQWNVSEYPGVKTVRFPDGQIWKPDILLYNSADE
  RFDATFHTNVLVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQHCKLKFGSWSYGGWSLDL
  QMQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIP
  CVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFAST
  MIIVGLSVVVTVIVLQYHHHDPDGGKMPKWTRVILLNWCAWFLRMKRPGEDKVRPACQHK
  QRRCSLASVEMSAVAPPPASNGNLLYIGFRGLDGVHCVPTPDSGVVCGRMACSPTHDEHL
  LHGGQPPEGDPDLAKILEEVRYIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTI
  ICTIGILMSAPNFVEAVSKDFA
• 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.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic synapse (hsa04725)
  Nicotine addiction (hsa05033)
  Chemical carcinogenesis (hsa05204)
• Reactome Pathway: Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALCURONIUM	DM2U4XQ	Anaesthesia	9A78.6	Approved	[2]
Ziprasidone	DMM58JY	Bipolar disorder	6A60	Approved	[1]

14 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 386	DMQJXL4	Breast cancer	2C60-2C65	Phase 3	[3]
CYTISINE	DMUF0BJ	Tobacco dependence	6C4A.2	Phase 3	[4]
EVP-6124	DMLQO7F	Alzheimer disease	8A20	Phase 3	[5]
ABT-126	DM2OS51	Alzheimer disease	8A20	Phase 2	[6]
AQW-051	DMD2RFO	Alzheimer disease	8A20	Phase 2	[7]
Bradanicline	DMZEECF	Chronic cough	MD12	Phase 2	[8]
GTS-21	DMEN5KA	Parkinson disease	8A00.0	Phase 2	[9]
JNJ-39393406	DMUOEKM	Depression	6A70-6A7Z	Phase 2	[10]
MEM-3454	DMPNDYU	Schizophrenia	6A20	Phase 2	[1]
TC-6987	DMNFP21	Asthma	CA23	Phase 2	[11]
AVL-3288	DMGAKR9	Cognitive impairment	6D71	Phase 1	[12]
BMS-933043	DMG3J6C	Psychiatric disorder	6E8Z	Phase 1	[13]
BNC375	DMI4UY3	Cognitive impairment	6D71	Phase 1	[14]
R4996	DMSKHIC	Neurological disorder	6B60	Phase 1	[3]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD-9684	DMHA5ME	Thrombosis	DB61-GB90	Discontinued in Phase 2	[15]
AZD0328	DM4B7CM	Alzheimer disease	8A20	Discontinued in Phase 2	[16]
ABT-107	DMPCYV6	Attention deficit hyperactivity disorder	6A05.Z	Discontinued in Phase 1	[17]
PNU-282987	DMGDC36	Schizophrenia	6A20	Terminated	[1]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PHA-568487	DMM149N	Cognitive impairment	6D71	Preclinical	[18]
RMG-40083	DMJGQD2	Schizophrenia	6A20	Preclinical	[1]

24 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3,8-dibromoboldine	DM23CEI	Discovery agent	N.A.	Investigative	[19]
3-bromoboldine	DMPF7O2	Discovery agent	N.A.	Investigative	[19]
4BP-TQS	DMS0JVE	Discovery agent	N.A.	Investigative	[20]
A-582941	DM7R8DJ	Discovery agent	N.A.	Investigative	[21]
A-867744	DM96F8U	Discovery agent	N.A.	Investigative	[22]
AZD-6319	DMD4YO9	Alzheimer disease	8A20	Investigative	[23]
Barbituric acid derivative	DM2I19P	Discovery agent	N.A.	Investigative	[24]
CP-810123	DMXDG13	Discovery agent	N.A.	Investigative	[25]
EVP-4473	DMHMFKE	Alzheimer disease	8A20	Investigative	[23]
GCCSHPACAGNNQHIC*	DM4BZEC	Discovery agent	N.A.	Investigative	[26]
GCCSNPVCHLEHSNLC*	DMJ0ICN	Discovery agent	N.A.	Investigative	[26]
JN-711	DMFU76I	Central nervous system disease	8A04-8D87	Investigative	[23]
JNJ-1930942	DMKH9O7	Cognitive impairment	6D71	Investigative	[23]
LY2087101	DMIS82X	Discovery agent	N.A.	Investigative	[27]
NS1738	DM2S5ZF	Discovery agent	N.A.	Investigative	[28]
PH-709829	DM5GY6Z	Discovery agent	N.A.	Investigative	[29]
PheTQS	DMWMBP3	Central nervous system disease	8A04-8D87	Investigative	[23]
PNU-120596	DMYBQM7	Discovery agent	N.A.	Investigative	[30]
PSAB-OFP	DM38JMK	Discovery agent	N.A.	Investigative	[31]
TOXIFERINE	DMJHTQK	Discovery agent	N.A.	Investigative	[2]
[125I]epibatidine	DMZWQH3	Discovery agent	N.A.	Investigative	[23]
[3H]A-585539	DMSDY2Z	Discovery agent	N.A.	Investigative	[32]
[3H]AZ11637326	DMPVG5Y	Discovery agent	N.A.	Investigative	[33]
[3H]methyllycaconitine	DMYWGCS	Discovery agent	N.A.	Investigative	[23]

References

• [1] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [2] 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.
• [3] Clinical pipeline report, company report or official report of Roche (2009).
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight
• [9] 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.
• [10] Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. Neuropharmacology. 2013 Jan;64:197-204.
• [11] ClinicalTrials.gov (NCT01293669) Glycemic Control, Safety and Tolerability of TC-6987 Monotherapy in Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
• [12] Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6(11):e27014.
• [13] Clinical pipeline report, company report or official report of Phrma.org Alzheimers 2012.
• [14] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [15] Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001 Apr;94(4):643-51.
• [16] 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.
• [17] 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.
• [18] Multiple species metabolism of PHA-568487, a selective alpha 7 nicotinic acetylcholine receptor agonist. Drug Metab Lett. 2010 Aug;4(3):162-72.
• [19] Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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. (Target id: 468).
• [24] Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
• [25] 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.
• [26] Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45.
• [27] Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006 Sep;318(3):1108-17.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] [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.
• [33] 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.