Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5KPZR)

• DTT Name: Neuronal acetylcholine receptor beta-2 (CHRNB2)
• Synonyms: Nicotinic acetylcholine receptor beta2; Nicotinic acetylcholine receptor beta 2-subunit protein; CHRNB2; Beta-2 nAChR; Alpha-4/beta-2 nicotinic receptor
• Gene Name: CHRNB2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: ACHB2_HUMAN
• TTD ID: T82543
• Sequence:
  MARRCGPVALLLGFGLLRLCSGVWGTDTEERLVEHLLDPSRYNKLIRPATNGSELVTVQL
  MVSLAQLISVHEREQIMTTNVWLTQEWEDYRLTWKPEEFDNMKKVRLPSKHIWLPDVVLY
  NNADGMYEVSFYSNAVVSYDGSIFWLPPAIYKSACKIEVKHFPFDQQNCTMKFRSWTYDR
  TEIDLVLKSEVASLDDFTPSGEWDIVALPGRRNENPDDSTYVDITYDFIIRRKPLFYTIN
  LIIPCVLITSLAILVFYLPSDCGEKMTLCISVLLALTVFLLLISKIVPPTSLDVPLVGKY
  LMFTMVLVTFSIVTSVCVLNVHHRSPTTHTMAPWVKVVFLEKLPALLFMQQPRHHCARQR
  LRLRRRQREREGAGALFFREAPGADSCTCFVNRASVQGLAGAFGAEPAPVAGPGRSGEPC
  GCGLREAVDGVRFIADHMRSEDDDQSVSEDWKYVAMVIDRLFLWIFVFVCVFGTIGMFLQ
  PLFQNYTTTTFLHSDHSAPSSK
• 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.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic synapse (hsa04725)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly sodium permeable acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CYTISINE	DMUF0BJ	Tobacco dependence	6C4A.2	Phase 3	[1]
TC-5214	DM8AM60	Palmar hyperhidrosis	EE00.00	Phase 2	[2]
SUVN-911	DMLPBVF	Major depressive disorder	6A70.3	Phase 1	[3]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-418	DMNP72I	Alzheimer disease	8A20	Discontinued in Phase 2	[4]
ABT-594	DMGMBCW	N. A.	N. A.	Discontinued in Phase 2	[5]
AZD-9684	DMHA5ME	Thrombosis	DB61-GB90	Discontinued in Phase 2	[6]
HOMOEPIBATIDINE	DMHP9WV	N. A.	N. A.	Terminated	[1]

25 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol	DMDUI8R	Discovery agent	N.A.	Investigative	[7]
(2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol	DMDUGZS	Discovery agent	N.A.	Investigative	[7]
3-[2-(N,N,N-trimethylammonium)ethoxy]pyridine	DMJB1KL	Discovery agent	N.A.	Investigative	[8]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[9]
6'-methylepibatidine	DMTG8D0	Discovery agent	N.A.	Investigative	[10]
A-867744	DM96F8U	Discovery agent	N.A.	Investigative	[11]
BOLDINE	DMMVB5P	Discovery agent	N.A.	Investigative	[12]
CMI-489	DM4PWDJ	Discovery agent	N.A.	Investigative	[10]
GCCSHPACAGNNQHIC*	DM4BZEC	Discovery agent	N.A.	Investigative	[13]
GCCSNPVCHLEHSNLC*	DMJ0ICN	Discovery agent	N.A.	Investigative	[13]
LY2087101	DMIS82X	Discovery agent	N.A.	Investigative	[14]
N,N-dimethyl(pyridin-3-yl)methanamine	DM41C8E	Discovery agent	N.A.	Investigative	[15]
N,N-dimethyl-2-(pyridin-3-yloxy)ethanamine	DMMD9A0	Discovery agent	N.A.	Investigative	[15]
N,N-dimethyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMLX0PI	Discovery agent	N.A.	Investigative	[15]
N-ethyl-N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMMKSGL	Discovery agent	N.A.	Investigative	[15]
N-methyl-2-(pyridin-3-yloxy)ethanamine	DMXS43P	Discovery agent	N.A.	Investigative	[15]
N-methyl-4-(pyridin-3-yl)but-3-yn-1-amine	DMMNIRC	Discovery agent	N.A.	Investigative	[15]
N-methyl-N-(pyridin-3-ylmethyl)ethanamine	DMOP128	Discovery agent	N.A.	Investigative	[15]
NS1738	DM2S5ZF	Discovery agent	N.A.	Investigative	[16]
NS9283	DMWN8FU	Discovery agent	N.A.	Investigative	[17]
Predicentrine methiodide	DM2HN4D	Discovery agent	N.A.	Investigative	[12]
TC-2559	DMLNVH8	Discovery agent	N.A.	Investigative	[18]
[125I]epibatidine	DMZWQH3	Discovery agent	N.A.	Investigative	[19]
[3H]cytisine	DMVLRHW	Discovery agent	N.A.	Investigative	[19]
[3H]nicotine	DM9E2YI	Discovery agent	N.A.	Investigative	[19]

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	7.10E-08	-0.15	-0.85
Irritable bowel syndrome	DD91.0	Rectal colon tissue	4.99E-01	5.60E-03	0.04
Parkinson's disease	8A00.0	Substantia nigra tissue	3.22E-01	-0.05	-0.24

References

• [1] Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Nicotine, brain nicotinic receptors, and neuropsychiatric disorders. Arch Med Res. 2000 Mar-Apr;31(2):131-44.
• [5] The nicotinic acetylcholine receptor agonist ABT-594 increases FGF-2 expression in various rat brain regions. Neuroreport. 1999 Dec 16;10(18):3909-13.
• [6] Blockade and activation of the human neuronal nicotinic acetylcholine receptors by atracurium and laudanosine. Anesthesiology. 2001 Apr;94(4):643-51.
• [7] Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 2010 Jun 24;53(12):4731-48.
• [8] Aryloxyethylamines: binding at alpha7 nicotinic acetylcholine receptors. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4283-6.
• [9] Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [10] Synthesis and nicotinic acetylcholine receptor binding properties of bridged and fused ring analogues of epibatidine. J Med Chem. 2007 Dec 13;50(25):6383-91.
• [11] 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.
• [12] Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg Med Chem. 2007 May 15;15(10):3368-72.
• [13] Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. J Med Chem. 2005 Jul 28;48(15):4705-45.
• [14] Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006 Sep;318(3):1108-17.
• [15] Synthesis and analgesic activity of secondary amine analogues of pyridylmethylamine and positional isomeric analogues of ABT-594. Bioorg Med Chem Lett. 2006 Apr 1;16(7):2013-6.
• [16] 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.
• [17] alpha4beta2 neuronal nicotinic receptor positive allosteric modulation: an approach for improving the therapeutic index of alpha4beta2 nAChR agonists in pain. Biochem Pharmacol. 2011 Oct 15;82(8):959-66.
• [18] The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices. Neuropharmacology. 2003 Sep;45(3):334-44.
• [19] 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: 465).