Target Information

Target General Information

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Target ID

T73724 (Former ID: TTDR00164)

Target Name

Neuronal acetylcholine receptor beta-4 (CHRNB4)

Synonyms

CHRNB4; Beta-4 nAChR

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Gene Name

CHRNB4

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

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.

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BioChemical Class

Neurotransmitter receptor

UniProt ID

ACHB4_HUMAN

Sequence

MRRAPSLVLFFLVALCGRGNCRVANAEEKLMDDLLNKTRYNNLIRPATSSSQLISIKLQL
SLAQLISVNEREQIMTTNVWLKQEWTDYRLTWNSSRYEGVNILRIPAKRIWLPDIVLYNN
ADGTYEVSVYTNLIVRSNGSVLWLPPAIYKSACKIEVKYFPFDQQNCTLKFRSWTYDHTE
IDMVLMTPTASMDDFTPSGEWDIVALPGRRTVNPQDPSYVDVTYDFIIKRKPLFYTINLI
IPCVLTTLLAILVFYLPSDCGEKMTLCISVLLALTFFLLLISKIVPPTSLDVPLIGKYLM
FTMVLVTFSIVTSVCVLNVHHRSPSTHTMAPWVKRCFLHKLPTFLFMKRPGPDSSPARAF
PPSKSCVTKPEATATSTSPSNFYGNSMYFVNPASAASKSPAGSTPVAIPRDFWLRSSGRF
RQDVQEALEGVSFIAQHMKNDDEDQSVVEDWKYVAMVVDRLFLWVFMFVCVLGTVGLFLP
PLFQTHAASEGPYAAQRD

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

CYTISINE

Drug Info

Phase 3

Tobacco dependence

[2]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

SIB-1553A

Drug Info

Discontinued in Phase 2

Alzheimer disease

[3]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 14 Inhibitor drugs

CYTISINE

Drug Info

[1]

HOMOEPIBATIDINE

Drug Info

[5]

(2S,3S)-2-(m-Tolyl)-3,5,5-trimethylmorpholin-2-ol

Drug Info

[6]

(2S,3S)-2-Phenyl-3,5,5-trimethylmorpholin-2-ol

Drug Info

[6]

15-nor-18-Methoxycornaridine

Drug Info

[7]

18-Dimethylaminocoronaridine

Drug Info

[7]

18-methoxycoronaridinate 2-Hydroxyethylamide

Drug Info

[7]

18-methoxycoronaridinate 2-methoxyethylamide

Drug Info

[7]

18-Methylaminocoronaridine

Drug Info

[7]

2-Acetylaminoethyl 18-methoxycoronaridinate

Drug Info

[7]

2-Hydroxyethyl 18-methoxycoronaridinate

Drug Info

[7]

2-Methoxyethyl 18-methoxycoronaridinate

Drug Info

[7]

GCCSNPVCHLEHSNLC*

Drug Info

[8]

N,N-Dimethylaminoethyl 18-methoxycoronaridinate

Drug Info

[7]

Agonist

[+] 1 Agonist drugs

SIB-1553A

Drug Info

[4]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Nicotine

Ligand Info

Structure Description

Human alpha3beta4 nicotinic acetylcholine receptor in complex with nicotine

PDB:6PV7

Method

Electron microscopy

Resolution

3.34 Å

Mutation

[9]

PDB Sequence

RVANAEEKLM

¹⁰

DDLLNKTRYN

²⁰

NLIRPATSSS

³⁰

QLISIKLQLS

⁴⁰

LAQLISVNER

⁵⁰

EQIMTTNVWL

⁶⁰

KQEWTDYRLT

⁷⁰

WNSSRYEGVN

⁸⁰

ILRIPAKRIW

⁹⁰

LPDIVLYNNA

¹⁰⁰

DGTYEVSVYT

¹¹⁰

NLIVRSNGSV

¹²⁰

LWLPPAIYKS

¹³⁰

ACKIEVKYFP

¹⁴⁰

FDQQNCTLKF

¹⁵⁰

RSWTYDHTEI

¹⁶⁰

DMVLMTPTAS

¹⁷⁰

MDDFTPSGEW

¹⁸⁰

DIVALPGRRT

¹⁹⁰

VNPQDPSYVD

²⁰⁰

VTYDFIIKRK

²¹⁰

PLFYTINLII

²²⁰

PCVLTTLLAI

²³⁰

LVFYLPSDCG

²⁴⁰

EKMTLCISVL

²⁵⁰

LALTFFLLLI

²⁶⁰

SKIVPPTSLD

²⁷⁰

VPLIGKYLMF

²⁸⁰

TMVLVTFSIV

²⁹⁰

TSVCVLNVHH

³⁰⁰

RSPSTHTMAP

³¹⁰

WVKRCFLHKL

³²⁰

PTFLFMKRRQ

⁴⁰¹

DVQEALEGVS

⁴¹¹

FIAQHMKNDD

⁴²¹

EDQSVVEDWK

⁴³¹

YVAMVVDRLF

⁴⁴¹

LWVFMFVCVL

⁴⁵¹

GTVGLFLP

Residue

Distance (Å)

TRP59

3.683

ILE113

3.595

Residue

Distance (Å)

LEU121

4.068

LEU123

3.862

Ligand Name: Cholesterol hemisuccinate

Ligand Info

Structure Description

Human alpha3beta4 nicotinic acetylcholine receptor in complex with nicotine

PDB:6PV7

Method

Electron microscopy

Resolution

3.34 Å

Mutation

[9]

PDB Sequence

RVANAEEKLM

¹⁰

DDLLNKTRYN

²⁰

NLIRPATSSS

³⁰

QLISIKLQLS

⁴⁰

LAQLISVNER

⁵⁰

EQIMTTNVWL

⁶⁰

KQEWTDYRLT

⁷⁰

WNSSRYEGVN

⁸⁰

ILRIPAKRIW

⁹⁰

LPDIVLYNNA

¹⁰⁰

DGTYEVSVYT

¹¹⁰

NLIVRSNGSV

¹²⁰

LWLPPAIYKS

¹³⁰

ACKIEVKYFP

¹⁴⁰

FDQQNCTLKF

¹⁵⁰

RSWTYDHTEI

¹⁶⁰

DMVLMTPTAS

¹⁷⁰

MDDFTPSGEW

¹⁸⁰

DIVALPGRRT

¹⁹⁰

VNPQDPSYVD

²⁰⁰

VTYDFIIKRK

²¹⁰

PLFYTINLII

²²⁰

PCVLTTLLAI

²³⁰

LVFYLPSDCG

²⁴⁰

EKMTLCISVL

²⁵⁰

LALTFFLLLI

²⁶⁰

SKIVPPTSLD

²⁷⁰

VPLIGKYLMF

²⁸⁰

TMVLVTFSIV

²⁹⁰

TSVCVLNVHH

³⁰⁰

RSPSTHTMAP

³¹⁰

WVKRCFLHKL

³²⁰

PTFLFMKRRQ

⁴⁰¹

DVQEALEGVS

⁴¹¹

FIAQHMKNDD

⁴²¹

EDQSVVEDWK

⁴³¹

YVAMVVDRLF

⁴⁴¹

LWVFMFVCVL

⁴⁵¹

GTVGLFLP

Residue

Distance (Å)

LEU227

3.749

ILE230

3.836

LEU231

4.392

TYR234

3.657

PHE287

4.996

VAL290

4.660

THR291

4.606

CYS294

3.633

VAL298

4.444

Residue

Distance (Å)

TRP311

4.276

VAL312

4.830

PHE316

3.541

VAL437

4.283

ARG439

3.464

PHE441

3.560

LEU442

4.138

TRP443

3.686

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Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Cholinergic synapse	hsa04725	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Cholinergic synapse

Panther Pathway

[+] 2 Panther Pathways

Nicotinic acetylcholine receptor signaling pathway

Nicotine pharmacodynamics pathway

Reactome

[+] 3 Reactome Pathways

Highly sodium permeable acetylcholine nicotinic receptors

Highly calcium permeable postsynaptic nicotinic acetylcholine receptors

Highly calcium permeable nicotinic acetylcholine receptors

WikiPathways

[+] 3 WikiPathways

SIDS Susceptibility Pathways

Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell

Nicotine Activity on Chromaffin Cells

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Deconstructing cytisine: The syntheses of (+/-)-cyfusine and (+/-)-cyclopropylcyfusine, fused ring analogs of cytisine. Bioorg Med Chem Lett. 2008 Apr 1;18(7):2316-9.

REF 2

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

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800009631)

REF 4

SIB-1553A, (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride, a subtype-selective ligand for nicotinic acetylcholine receptors with putative cognitive-enhancing properties: effectson working and reference memory performances in aged rodents and nonhuman primates. J Pharmacol Exp Ther. 2001 Oct;299(1):297-306.

REF 5

Epibatidine isomers and analogues: structure-activity relationships. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5493-7.

REF 6

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.

REF 7

Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents. J Med Chem. 2003 Jun 19;46(13):2716-30.

REF 8

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

REF 9

Agonist Selectivity and Ion Permeation in the Alpha3beta4 Ganglionic Nicotinic Receptor. Neuron. 2019 Nov 6;104(3):501-511.e6.

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