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] 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 (k_i=1 nM), which is also the 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)

Ligands

Agonists

• 3-Bromocytisine
• Acetylcholine
• Cytisine
• Galantamine
• Epibatidine
• Nicotine
• A-84,543
• A-366,833
• ABT-418
• 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^[6]
• N-(3-pyridinyl)-bridged bicyclic diamines^[7][8][9]

PAMs

• NS-9283: 60-fold left-shifting of concentration-response curve, no change in maximum efficacy^[10]
• Desformylflustrabromine^[11]
• Further compounds.. (see references →)^[12][13]

Antagonists

• (−)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane^[14]
• 2-fluoro-3-(4-nitro-phenyl)deschloroepibatidine^[15]
• Coclaurine - alkaloid from Nelumbo nucifera^[16]
• Mecamylamine^[17]
• α-Conotoxin
• PNU-120,596

See also

• α3β2-Nicotinic receptor
• α3β4-Nicotinic receptor
• α7-Nicotinic receptor

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.
2. Rang; Dale; Ritter; Moore (2003). Pharmacology (5th ed.). Churchill Livingstone. p. 138. ISBN 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.
5. "Nicotine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 7 February 2016. K_is 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. 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. doi:10.1124/mol.108.045104. PMID 18367540.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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. doi:10.1124/jpet.108.146910. PMID 18957576.