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Alpha-4 beta-2 nicotinic receptor

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Title: Alpha-4 beta-2 nicotinic receptor  
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Subject: Epibatidine, UB-165, Epiboxidine, GTS-21, Sazetidine A
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Alpha-4 beta-2 nicotinic receptor

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]

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)





See also


  1. ^ Cordero-Erausquin, M; Marubio, LM; Klink, R; Changeux, JP (2000). "Nicotinic receptor function: new perspectives from knockout mice". Trends Pharmacol Sci. 21 (6): 211–7.  
  2. ^ a b Rang; Dale; Ritter; Moore (2003). Pharmacology (5th ed.). Churchill Livingstone. p. 138.  
  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.  
  4. ^ Zwart, R.; Carbone, A. L.; Moroni, M.; Bermudez, I.; Mogg, A. J.; Folly, E. A.; Broad, L. M.; Williams, A. C.; Zhang, D.; Ding, C.; Heinz, B. A.; Sher, E. (2008). "Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors". Mol. Pharmacol. 73 (6): 1838–43.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ 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.  
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ Fedorov, N. B.; Benson, L. C.; Graef, J.; Lippiello, P. M.; Bencherif, M. (February 2009). "Differential pharmacologies of mecamylamine enantiomers: positive allosteric modulation and noncompetitive inhibition". J. Pharmacol. Exp. Ther. 328 (2): 525–32.  

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