The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

implicated in learning, consisting of α4 and β2 subunits. It is located in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

, where activation yields

post- ''Post-'' (stylized in all caps) is the third solo studio album by American singer-songwriter Jeff Rosenstock, released on January 1, 2018, without any promotional lead-up. The album was released on Polyvinyl Record Co. in the United States and ...

and presynaptic excitation, mainly by increased Na⁺ and K⁺ permeability. Stimulation of this receptor subtype is also associated with

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

secretion. People with the inactive CHRNA4 mutation Ser248Phe are an average of 10 cm (4 inches) shorter than average and predisposed to

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. A 2015 review noted that stimulation of the α4β2 nicotinic receptor in the brain is responsible for certain improvements in attentional performance; among the nicotinic receptor subtypes,

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

has the highest

binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...

at the α4β2 receptor (k_i=1 ), which is also the primary biological target that mediates nicotine's addictive properties. The receptors exist in the two stoichiometries: *(α4)₂(β2)₃ receptors have high sensitivity to

and low Ca²⁺ permeability (HS receptors) *(α4)₃(β2)₂ receptors have low sensitivity to nicotine and high Ca²⁺ permeability (LS receptors)

Structure

The α4β2 receptor assemble in two distinct stoichiometric forms. One stoichiometry contains three α4 and two β2 subunits (α4)₃(β2)₂ whereas the other stoichiometry contains two α4 and three β2 (α4)₂(β2)₃ The x-ray structure of the (α4)₂(β2)₃ receptor is known since 2016 and reveals a circular α–β–β–α–β ordering of subunits.

Ligands

Source:

Agonists

* 3-Bromocytisine *

Acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

Cytisine Cytisine, also known as baptitoxine, cytisinicline, or sophorine, is an alkaloid that occurs naturally in several plant genera, such as '' Laburnum'' and '' Cytisus'' of the family Fabaceae. It has been used medically to help with smoking cessa ...

Galantamine Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of ''Galanthus nivalis'' (common snowdrop), '' Galanthus caucasicus'' (Caucasian snowdrop), '' Galanthus woronowii'' (Voronov's snow ...

Epibatidine Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog '' Epipedobates anthonyi'' and poison dart frogs from the ''Ameerega'' genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated u ...

* Epiboxidine *

Nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

A-84,543 } A-84543 is a drug developed by Abbott, which acts as an agonist at neural nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitte ...

A-366,833 A-366,833 is a drug developed by Abbott, which acts as an agonist at neural nicotinic acetylcholine receptors selective for the α4β2 subtype, and has been researched for use as an analgesic, although it has not passed clinical trials Clin ...

ABT-418 ABT-418 is a drug developed by Abbott, that has nootropic, neuroprotective and anxiolytic effects, and has been researched for treatment of both Alzheimer's disease and ADHD. It acts as an agonist at neural nicotinic acetylcholine receptors, ...

Arecoline Arecoline is a cholinergic agent, stimulant, and natural product, naturally occurring alkaloid found in areca nut, areca (betel) nuts of the areca palm (''Areca catechu'') found in South Asia, South and Southeast Asia. Its effects, depending on ...

Altinicline Altinicline (SIB-1508Y, SIB-1765F) is a drug which acts as an agonist at neural nicotinic acetylcholine receptors with high selectivity for the α4β2 subtype. It stimulates release of dopamine and acetylcholine in the brain in both rodent and p ...

Dianicline Dianicline (SSR-591,813) is a drug developed by Sanofi-Aventis which acts as a partial agonist at neural nicotinic acetylcholine receptors. It is subtype-selective, binding primarily to the α4β2 subtype. It is being developed as a medication ...

Ispronicline Ispronicline (TC-1734, AZD-3480) is an experimental drug which acts as a partial agonist at neural nicotinic acetylcholine receptors. It progressed to phase II clinical trials for the treatment of dementia and Alzheimer's disease, but is no lon ...

Pozanicline Pozanicline (INN, codenamed ABT-089) is a drug developed by Abbott, that has nootropic and neuroprotective effects. Animal studies suggested it useful for the treatment of ADHD and subsequent human trials have shown ABT-089 to be effective for ...

* Rivanicline * Tebanicline * TC-1827 * Varenicline * Sazetidine A: full agonist on (α4)₂(β2)₃, 6% efficacy on (α4)₃(β2)₂ *''N''-(3-pyridinyl)-bridged bicyclic diamines

PAMs

* NS-9283: 60-fold left-shifting of concentration-response curve, no change in maximum efficacy * Desformylflustrabromine * Further compounds.. (see references →)

Antagonists

* (−)-7-methyl-2-exo- '-(6-[18Fluoropyridin-2-yl)-5'-pyridinyl">8F.html" ;"title="'-(6-[18F">'-(6-[18Fluoropyridin-2-yl)-5'-pyridinyl7-azabicyclo[2.2.1]heptane * 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine * Coclaurine - alkaloid from ''Nelumbo nucifera'' * Mecamylamine * α-Conotoxin * PNU-120,596 *

Bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

* Dihydro-β-erythroidine, selective *

Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or factitious air, among others, is a chemical compound, an Nitrogen oxide, oxide of nitrogen with the Chemical formula, formula . At room te ...

Isoflurane Isoflurane, sold under the brand name Forane among others, is a halogenated ether used as a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritat ...

*1-(6-(((''R'',''S'')-7-Hydroxychroman-2-yl)methylamino]hexyl)-3-((''S'')-1-methylpyrrolidin-2-yl)pyridinium bromide (compound 2) ( Ligand (biochemistry)#Bivalent ligand, heterobivalent ligand: D2R agonist and

nAChR Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

antagonist)

NAMs

* Oxantel

References

{{Nicotinic acetylcholine receptor modulators Ion channels Addiction Nicotinic acetylcholine receptors