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 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 n ...

implicated in learning, consisting of α4 and β2

subunit Subunit may refer to: *Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer *Sub-subunit, a ...

s. It is located in the

brain The brain is an 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 special ...

, where activation yields

post- ''Post-'' (stylized in all caps) is the third solo album by American singer-songwriter Jeff Rosenstock. It was 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 Neuronal acetylcholine receptor subunit alpha-4, also known as nAChRα4, is a protein that in humans is encoded by the ''CHRNA4'' gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAChR). Alpha4-cont ...

mutation Ser248Phe are an average of 10 cm (4 inches) shorter than average and predisposed to

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

. 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 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 ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mo ...

at the α4β2 receptor (k_i=1 ), which is also the primary biological target that mediates nicotine's

addictive Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...

properties. The receptors exist in the two stoichiometries: *(α4)₂(β2)₃ receptors have high sensitivity to nicotine 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

Agonists

3-Bromocytisine 3-Bromocytisine is a derivative of the toxic alkaloid cytisine that acts as a highly potent agonist at neural nicotinic acetylcholine receptors, binding primarily to the α4β2 and α7 subtypes. 3-Bromocytisine is a full agonist at the α7 subty ...

Acetylcholine Acetylcholine (ACh) is an organic chemical 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 cess ...

Galantamine Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of '' Galanthus nivalis'' (Common 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 until 19 ...

Epiboxidine Epiboxidine is a chemical compound which acts as a partial agonist at neural nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes. It was developed as a less toxic analogue of the potent frog-derived alkaloid ep ...

* Nicotine * A-84,543 *

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. Its stru ...

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 nicotinic acid-based mild parasympathomimetic stimulant alkaloid found in the areca nut, the fruit of the areca palm ('' Areca catechu''). It is an odourless oily liquid. It can bring a sense of enhanced alertness and energy ...

* Altinicline *

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 fo ...

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 lo ...

* Pozanicline *

Rivanicline Rivanicline (TC-2403, RJR-2403, (E)-metanicotine) is a drug which acts as a partial agonist at neural nicotinic acetylcholine receptors. It is subtype-selective, binding primarily to the α4β2 subtype. It has nootropic effects and was originally ...

Tebanicline Tebanicline (ebanicline, ABT-594) is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analog of the potent poison dart frog-derived compound epibatidine, which is about 200 times strong ...

TC-1827 TC-1827 is an orally active, selective agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In con ...

Varenicline Varenicline (trade name Chantix and Champix) is a medication used for smoking cessation. Varenicline is also used for the treatment of dry eye disease. The most common side-effects include nausea (feeling sick), insomnia (difficulty sleeping), ...

Sazetidine A Sazetidine A (AMOP-H-OH) is a drug which acts as a subtype selective partial agonist at α4β2 neural nicotinic acetylcholine receptors, acting as an agonist at (α4)2(β2)3 pentamers, but as an antagonist at (α4)3(β2)2 pentamers. It has potent ...

: 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 Desformylflustrabromine (dFBr) is a monomethyl tryptamine derivative which was first isolated as a secondary metabolite of the marine bryozoan ''Flustra foliacea''. Bioactivity dFBr has been identified as a novel positive allosteric modulato ...

* 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 A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus ''Conus''. Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Cono ...

* PNU-120,596 *

Bupropion Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...

* Dihydro-β-erythroidine, selective *

Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has ...

Isoflurane Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...

*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 n ...

antagonist)

NAMs

Oxantel Oxantel is an anthelmintic. It has typically been used in human and animal medicine as a treatment for intestinal worms. Oxantel has been shown to inhibit fumarate reductase Fumarate reductase is the enzyme that converts fumarate to succinate, ...

References

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