Alpha-7 nicotinic receptor
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Alpha-7 nicotinic receptor
The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor, consisting entirely of α7 subunits.[1]. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].
It is located in the brain, lymphocyte and spleen where activation yields post- and presynaptic excitation[1], mainly by increased Ca2+ permeability.
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Contents
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Medical Relevance
Recent work has demonstrated a potential role in reducing inflamatory neurotoxicity in stroke, MI, sepsis, and alzheimers disease.[1][2][3]
[1]Acetylcholine-Synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit
Science DOI: 10.1126/science.1209985
Mauricio Rosas-Ballina1,*, Peder S. Olofsson1,*, Mahendar Ochani1, Sergio I. Valdés-Ferrer1,2, Yaakov A. Levine1, Colin Reardon3, Michael W. Tusche3, Valentin A. Pavlov1, Ulf Andersson4, Sangeeta Chavan1, Tak W. Mak3, Kevin J. Tracey
[2] J Clin Invest. 2007 Feb;117(2):289-96. Physiology and immunology of the cholinergic antiinflammatory pathway. Tracey KJ. http://www.ncbi.nlm.nih.gov/pubmed/17273548
[3] The Journal of Neuroscience, 2 March 2011, 31(9): 3446-3452; doi: 10.1523/?JNEUROSCI.4558-10.2011
Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-Inflammatory Processes: A Role for Cholinergic ?7 Nicotinic Receptors Greg J. Norman1, John S. Morris1, Kate Karelina2, Zachary M. Weil2, Ning Zhang2, Yousef Al-Abed3, Holly M. Brothers1, Gary L. Wenk1, Valentin A. Pavlov3, Kevin J. Tracey3, and A. Courtney DeVries2
http://www.jneurosci.org/content/31/9/3446.full.pdf
Ligands
Agonists
- (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan- 2-carboxamide: potent and highly subtype-selective[2]
- A-582941: partial agonist; activates ERK1/2 and CREB phosphorylation; enhances cognitive performance[3]
- AR-R17779: full agonist, nootropic
- TC-1698: subtype-selective; neuroprotective effects via activation of the JAK2/PI-3K cascade, neutralized by angiotensin II AT(2) receptor activation[4]
- TC-5619 - partial agonist, in development for treatment of schizophrenia
- GTS-21 - partial agonist, in development for treatment of schizophrenia and/or Alzheimer's disease
- PHA-543,613
- PNU-282,987
- PHA-709829: potent and subtype-selective; robust in vivo efficacy in a rat auditory sensory gating model[5]
- SSR-180,711: partial agonist[7]
- Tropisetron: subtype-selective partial agonist; 5-HT3 receptor antagonist[8]
- WAY-317,538
- Anabaseine
- Choline
- Nicotine
PAMs
At least two types of positive allosteric modulators (PAMs) can be distinguished.[9]
- PNU-120,596[10]
- NS-1738: marginal effects on α7 desensitization kinetics; modestly brain-penetrant[11]
- AVL-3288: unlike the above PAMs, AVL-3288 does not affect α7 desensitization kinetics, and is readily brain penetrant. Improves cognitive behavior in animal models[12] In clinical development for cognitive deficits in schizophrenia.
- A-867744[13][14]
- Ivermectin
- Galantamine
Antagonists
- α-conotoxin ArIB[V11L,V16D]: potent and highly subtype-selective; slowly reversible[15]
- Memantine
- Quinolizidine (–)-1-epi-207I: α7 subtype preferring blocker[16]
See also
References
- ^ a b Pharmacology, (Rang, Dale, Ritter & Moore, ISBN 0-443-07145-4, 5:th ed., Churchill Livingstone 2003) Page 138.
- ^ Mazurov A, Klucik J, Miao L, et al. (2005). "2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands". Bioorg. Med. Chem. Lett. 15 (8): 2073–7. doi:10.1016/j.bmcl.2005.02.045. PMID 15808471.
- ^ Tietje KR, Anderson DJ, Bitner RS, et al. (2008). "Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties". CNS Neurosci Ther 14 (1): 65–82. doi:10.1111/j.1527-3458.2008.00037.x. PMID 18482100.
- ^ Marrero MB, Papke RL, Bhatti BS, Shaw S, Bencherif M (2004). "The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase". J. Pharmacol. Exp. Ther. 309 (1): 16–27. doi:10.1124/jpet.103.061655. PMID 14722323.
- ^ Acker BA, Jacobsen EJ, Rogers BN, et al. (2008). "Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl] furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity". Bioorg. Med. Chem. Lett. 18 (12): 3611–5. doi:10.1016/j.bmcl.2008.04.070. PMID 18490160.
- ^ Walker DP, Wishka DG, Piotrowski DW, et al. (2006). "Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists". Bioorg. Med. Chem. 14 (24): 8219–48. doi:10.1016/j.bmc.2006.09.019. PMID 17011782.
- ^ Biton B, Bergis OE, Galli F, et al. (2007). "SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile". Neuropsychopharmacology 32 (1): 1–16. doi:10.1038/sj.npp.1301189. PMID 17019409.
- ^ Macor JE, Gurley D, Lanthorn T, et al. (2001). "The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist". Bioorg. Med. Chem. Lett. 11 (3): 319–21. doi:10.1016/S0960-894X(00)00670-3. PMID 11212100. http://linkinghub.elsevier.com/retrieve/pii/S0960894X00006703.
- ^ Grønlien JH, Håkerud M, Ween H, et al. (2007). "Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes". Mol. Pharmacol. 72 (3): 715–24. doi:10.1124/mol.107.035410. PMID 17565004.
- ^ Hurst RS, Hajós M, Raggenbass M, et al. (2005). "A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization". J. Neurosci. 25 (17): 4396–405. doi:10.1523/JNEUROSCI.5269-04.2005. PMID 15858066.
- ^ Timmermann DB, Grønlien JH, Kohlhaas KL, et al. (2007). "An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo". J. Pharmacol. Exp. Ther. 323 (1): 294–307. doi:10.1124/jpet.107.120436. PMID 17625074.
- ^ Ng, HJ, et al. (2007). "Nootropic α7 nicotinic receptor allosteric modulator derived from GABA A receptor modulators". PNAS 104 (19): 8059–8064. doi:10.1073/pnas.0701321104. PMC 1876571. PMID 701321104. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1876571.
- ^ Faghih R, Gopalakrishnan SM, Gronlien JH, et al. (May 2009). "Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor". J. Med. Chem. 52 (10): 3377–84. doi:10.1021/jm9003818. PMID 19419141.
- ^ Malysz J, Gronlien JH, Anderson DJ, et al. (April 2009). "In vitro pharmacological characterization of a novel allosteric modulator of {alpha}7 nAChR, A-867744, exhibiting unique pharmacological profile". J. Pharmacol. Exp. Ther. 330 (1): 257–67. doi:10.1124/jpet.109.151886. PMID 19389923.
- ^ Whiteaker P, Christensen S, Yoshikami D, et al. (2007). "Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist". Biochemistry 46 (22): 6628–38. doi:10.1021/bi7004202. PMID 17497892.
- ^ Tsuneki H, You Y, Toyooka N, et al. (2004). "Alkaloids indolizidine 235B', quinolizidine 1-epi-207I, and the tricyclic 205B are potent and selective noncompetitive inhibitors of nicotinic acetylcholine receptors". Mol. Pharmacol. 66 (4): 1061–9. doi:10.1124/mol.104.000729. PMID 15258256.
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