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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

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

Source: [7]

Agonists

PAMs

Antagonists

NAMs

See also

References

  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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  11. ^ Bunnelle, William H.; Daanen, Jerome F.; Ryther, Keith B.; Schrimpf, Michael R.; Dart, Michael J.; Gelain, Arianna; Meyer, Michael D.; Frost, Jennifer M.; Anderson, David J.; Buckley, Michael; Curzon, Peter; Cao, Ying-Jun; Puttfarcken, Pamela; Searle, Xenia; Ji, Jianguo; Putman, C. Brent; Surowy, Carol; Toma, Lucio; Barlocco, Daniela (2007). "Structure-activity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors". J. Med. Chem. 50 (15): 3627–44. doi: 10.1021/jm070018l. PMID  17585748.
  12. ^ Frost (Née Pac, Jennifer M.; Bunnelle, William H.; Tietje, Karin R.; Anderson, David J.; Rueter, Lynne E.; Curzon, Peter; Surowy, Carol S.; Ji, Jianquo; Daanen, Jerome F.; Kohlhaas, Kathy L.; Buckley, Michael J.; Henry, Rodger F.; Dyhring, Tino; Ahring, Philip K.; Meyer, Michael D. (2006). "Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists". J. Med. Chem. 49 (26): 7843–53. doi: 10.1021/jm060846z. PMID  17181167.
  13. ^ Ji, Jianguo; Schrimpf, Michael R.; Sippy, Kevin B.; Bunnelle, William H.; Li, Tao; Anderson, David J.; Faltynek, Connie; Surowy, Carol S.; Dyhring, Tino; Ahring, Philip K.; Meyer, Michael D. (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. 50 (22): 5493–508. doi: 10.1021/jm070755h. PMID  17929796.
  14. ^ Grupe, M; Jensen, AA; Ahring, PK; Christensen, JK; Grunnet, M (2013). "Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors". British Journal of Pharmacology. 168 (8): 2000–10. doi: 10.1111/bph.12095. PMC  3623068. PMID  23278456.
  15. ^ Kim, Jin-Sung; Padnya, Anshul; Weltzin, Maegan; Edmonds, Brian W.; Schulte, Marvin K.; Glennon, Richard A. (2007). "Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator". Bioorg. Med. Chem. Lett. 17 (17): 4855–60. doi: 10.1016/j.bmcl.2007.06.047. PMC  3633077. PMID  17604168.
  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.
  19. ^ Abdrakhmanova, G. R.; Damaj, M. I.; Carroll, F. I.; Martin, B. R. (2006). "2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent competitive antagonist of human neuronal alpha4beta2 nAChRs". Mol. Pharmacol. 69 (6): 1945–52. doi: 10.1124/mol.105.021782. PMID  16505153. S2CID  96557182.
  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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