Alpha-4 beta-2 nicotinic receptor

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The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of nicotinic acetylcholine receptor implicated in learning,[1] consisting of α4 and β2 subunits.[2] It is located in the brain, where activation yields post- and presynaptic excitation,[2] mainly by increased Na+ and K+ permeability.

Stimulation of this receptor subtype is also associated with growth hormone secretion. People with the inactive CHRNA4 mutation Ser248Phe are an average of 10 cm (4 inches) shorter than average and predisposed to obesity.[3] A 2015 review noted that stimulation of the α4β2 nicotinic receptor in the brain is responsible for certain improvements in attentional performance;[4] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the primary biological target that mediates nicotine's addictive properties.[5]

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[edit]

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[6] and reveals a circular α–β–β–α–β ordering of subunits.

Ligands[edit]

Source:[7]

Agonists[edit]

PAMs[edit]

Antagonists[edit]

NAMs[edit]

See also[edit]

References[edit]

  1. ^ Cordero-Erausquin, M; Marubio, LM; Klink, R; Changeux, JP (2000). "Nicotinic receptor function: new perspectives from knockout mice" (PDF). Trends Pharmacol. Sci. 21 (6): 211–7. doi:10.1016/S0165-6147(00)01489-9. PMID 10838608. Archived from the original (PDF) on 2014-05-15. Retrieved 2012-10-08.
  2. ^ a b Rang; Dale; Ritter; Moore (2003). Pharmacology (5th ed.). Churchill Livingstone. p. 138. ISBN 978-0-443-07145-4.
  3. ^ Fedi, M; Bach, LA; Berkovic, SF; Willoughby, JO; Scheffer, IE; Reutens, DC (2008). "Association of a nicotinic receptor mutation with reduced height and blunted physostigmine-stimulated growth hormone release". The Journal of Clinical Endocrinology and Metabolism. 93 (2): 634–7. doi:10.1210/jc.2007-1611. PMID 18042647.
  4. ^ Sarter M (August 2015). "Behavioral-cognitive targets for cholinergic enhancement". Current Opinion in Behavioral Sciences. 4: 22–26. doi:10.1016/j.cobeha.2015.01.004. PMC 5466806. PMID 28607947.
  5. ^ "Nicotine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 7 February 2016. Kis as follows; α2β4=9900nM [5], α3β2=14nM [1], α3β4=187nM [1], α4β2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α4β2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction [2-3].
  6. ^ Morales-Perez CL, Noviello CM, Hibbs RE (2016). "X-ray structure of the human α4β2 nicotinic receptor". Nature. 538 (7625): 411–415. doi:10.1038/nature19785. PMC 5161573. PMID 27698419.
  7. ^ Matera, Carlo; Papotto, Claudio; Dallanoce, Clelia; De Amici, Marco (2023-08-01). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors". Pharmacological Research. 194: 106813. doi:10.1016/j.phrs.2023.106813. hdl:2434/978688. ISSN 1043-6618.
  8. ^ Dallanoce, Clelia; Matera, Carlo; Amici, Marco De; Rizzi, Luca; Pucci, Luca; Gotti, Cecilia; Clementi, Francesco; Micheli, Carlo De (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. 24 (7): 543–551. doi:10.1002/chir.22052. ISSN 1520-636X. PMID 22566097.
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  16. ^ Albrecht, Brian K.; Berry, Virginia; Boezio, Alessandro A.; Cao, Lei; Clarkin, Kristie; Guo, Wenhong; Harmange, Jean-Christophe; Hierl, Markus; Huang, Liyue; Janosky, Brett; Knop, Johannes; Malmberg, Annika; McDermott, Jeff S.; Nguyen, Hung Q.; Springer, Stephanie K.; Waldon, Daniel; Woodin, Katrina; McDonough, Stefan I. (2008). "Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators". Bioorg. Med. Chem. Lett. 18 (19): 5209–12. doi:10.1016/j.bmcl.2008.08.080. PMID 18789861.
  17. ^ Springer, Stephanie K.; Woodin, Katrina S.; Berry, Virginia; Boezio, Alessandro A.; Cao, Lei; Clarkin, Kristie; Harmange, Jean-Christophe; Hierl, Markus; Knop, Johannes; Malmberg, Annika B.; McDermott, Jeff S.; Nguyen, Hung Q.; Waldon, Daniel; Albrecht, Brian K.; McDonough, Stefan I. (2008). "Synthesis and activity of substituted carbamates as potentiators of the alpha4beta2 nicotinic acetylcholine receptor". Bioorg. Med. Chem. Lett. 18 (20): 5643–7. doi:10.1016/j.bmcl.2008.08.092. PMID 18805006.
  18. ^ Gao, Yongjun; Kuwabara, Hiroto; Spivak, Charles E.; Xiao, Yingxian; Kellar, Kenneth; Ravert, Hayden T.; Kumar, Anil; Alexander, Mohab; Hilton, John; Wong, Dean F.; Dannals, Robert F.; Horti, Andrew G. (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. 51 (15): 4751–64. doi:10.1021/jm800323d. PMID 18605717.
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  20. ^ Kashiwada, Yoshiki; Aoshima, Akihiro; Ikeshiro, Yasumasa; Chen, Yuh-Pan; Furukawa, Hiroshi; Itoigawa, Masataka; Fujioka, Toshihiro; Mihashi, Kunihide; Cosentino, L. Mark; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung (2005). "Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure–activity correlations with related alkaloids". Bioorganic & Medicinal Chemistry. 13 (2): 443–8. doi:10.1016/j.bmc.2004.10.020. PMID 15598565.
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  22. ^ Matera, Carlo; Pucci, Luca; Fiorentini, Chiara; Fucile, Sergio; Missale, Cristina; Grazioso, Giovanni; Clementi, Francesco; Zoli, Michele; De Amici, Marco (2015-08-28). "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: Design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry. 101: 367–383. doi:10.1016/j.ejmech.2015.06.039. PMID 26164842.
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