Alpha-4 beta-2 nicotinic receptor

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
• Cytisine
• Galantamine
• Epibatidine
• Epiboxidine
• Nicotine
• A-84,543
• A-366,833
• ABT-418
• Arecoline
• Altinicline
• Dianicline
• Ispronicline
• Pozanicline
• 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-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane
• 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine
• Coclaurine - alkaloid from Nelumbo nucifera
• Mecamylamine
• α-Conotoxin
• PNU-120,596
• Bupropion
• Dihydro-β-erythroidine, selective
• Nitrous oxide
• Isoflurane
• 1-(6-(((R,S)-7-Hydroxychroman-2-yl)methylamino]hexyl)-3-((S)-1-methylpyrrolidin-2-yl)pyridinium bromide (compound 2) (heterobivalent ligand: D2R agonist and nAChR antagonist)

NAMs

• Oxantel

References

References

1. (2000). "Nicotinic receptor function: new perspectives from knockout mice". Trends Pharmacol. Sci..
2. (2003). "Pharmacology". Churchill Livingstone.
3. (2008). "Association of a nicotinic receptor mutation with reduced height and blunted physostigmine-stimulated growth hormone release". The Journal of Clinical Endocrinology and Metabolism.
4. (August 2015). "Behavioral-cognitive targets for cholinergic enhancement". Current Opinion in Behavioral Sciences.
5. "Nicotine: Biological activity". International Union of Basic and Clinical Pharmacology.
6. (2016). "X-ray structure of the human α4β2 nicotinic receptor". Nature.
7. (2023-08-01). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors". Pharmacological Research.
8. (2012-07-01). "The enantiomers of epiboxidine and of two related analogs: Synthesis and estimation of their binding affinity at α4β2 and α7 neuronal nicotinic acetylcholine receptors". Chirality.
9. (August 2021). "Nicotinic aspects of the discriminative stimulus effects of arecoline". [[Behavioural Pharmacology]].
10. (2008). "Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors". Mol. Pharmacol..
11. (2007). "Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors". J. Med. Chem..
12. (2006). "Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists". J. Med. Chem..
13. (2007). "Synthesis and structure-activity relationship studies of 3,6-diazabicyclo[3.2.0]heptanes as novel alpha4beta2 nicotinic acetylcholine receptor selective agonists". J. Med. Chem..
14. (2013). "Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors". British Journal of Pharmacology.
15. (2007). "Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator". Bioorg. Med. Chem. Lett..
16. (2008). "Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators". Bioorg. Med. Chem. Lett..
17. (2008). "Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor". Bioorg. Med. Chem. Lett..
18. (2008). "Discovery of (−)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties". J. Med. Chem..
19. (2006). "2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent competitive antagonist of human neuronal alpha4beta2 nAChRs". Mol. Pharmacol..
20. (2005). "Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure–activity correlations with related alkaloids". Bioorganic & Medicinal Chemistry.
21. (February 2009). "Differential pharmacologies of mecamylamine enantiomers: positive allosteric modulation and noncompetitive inhibition". J. Pharmacol. Exp. Ther..
22. (2015-08-28). "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: Design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry.
23. (2012). "Specificity determinants of allosteric modulation in the neuronal nicotinic acetylcholine receptor: a fine line between inhibition and potentiation". Mol. Pharmacol..