Biology:Alpha-7 nicotinic receptor
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The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, 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, spleen, and lymphocytes of lymph nodes where activation yields post- and presynaptic excitation,[1] mainly by increased Ca2+ permeability.
Further, recent work has implicated this receptor as being important for generation of adult mammal neurons in the retina.[2] Functional α7 receptors are present in the submucous plexus neurons of the guinea-pig ileum.[3]
Medical relevance
Recent work has demonstrated a potential role in reducing inflammatory neurotoxicity in stroke, myocardial infarction, sepsis, and Alzheimer's disease.[4][5][6]
An α7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia.[7]
Activation of α7 nicotinic acetylcholine receptor on mast cells, is a mechanism by which nicotine enhances atherosclerosis.[8]
Both α4β2 and α7 nicotinic receptors appear to be critical for memory, working memory, learning, and attention.[9]
α7-nicotinic receptors also appear to be involved in cancer progression. They have been shown to mediate cancer cell proliferation and metastasis.[10] α7 receptors are also involved in angiogenic and neurogenic activity, and have anti-apoptotic effects.[11][12][13]
Ligands
Agonists
- (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan- 2-carboxamide: potent and highly subtype-selective[14]
- Tilorone.
- A-582941: partial agonist; activates ERK1/2 and CREB phosphorylation; enhances cognitive performance[15]
- AR-R17779: full agonist, nootropic
- Amyloid beta: neurotoxic marker of Alzheimer's disease[16]
- TC-1698: subtype-selective; neuroprotective effects via activation of the JAK2/PI-3K cascade, neutralized by angiotensin II AT(2) receptor activation[17]
- Bradanicline - partial agonist, in development for treatment of schizophrenia
- Encenicline - partial agonist with nootropic properties, in development for treatment of schizophrenia and Alzheimer's disease [18][19]
- GTS-21 - partial agonist, in development for treatment of schizophrenia and/or Alzheimer's disease
- PHA-543,613 - selective and potent agonist with nootropic properties [20][21]
- PNU-282,987 - selective and potent agonist, but may cause long QT syndrome
- PHA-709829: potent and subtype-selective; robust in vivo efficacy in a rat auditory sensory gating model[22]
- SSR-180,711: partial agonist[24]
- Tropisetron: subtype-selective partial agonist; 5-HT3 receptor antagonist[25]
- WAY-317,538 - selective potent full agonist with nootropic and neuroprotective properties
- Anabasine
- Acetylcholine
- Nicotine
- Epiboxidine[26]
- Choline[27]
- ICH-3: subtype-selective partial agonist[28]
Positive Allosteric Modulators (PAMs)
At least two types of positive allosteric modulators (PAMs) can be distinguished.[29]
- PNU-120,596[30]
- NS-1738: marginal effects on α7 desensitization kinetics; modestly brain-penetrant[31]
- 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[32] In clinical development for cognitive deficits in schizophrenia.
- A-867744[33][34]
- Ivermectin
Other
Antagonists
It is found that anandamide and ethanol cause an additive inhibition on the function of α7-receptor by interacting with distinct regions of the receptor. Although ethanol inhibition of the α7-receptor is likely to involve the N-terminal region of the receptor, the site of action for anandamide is located in the transmembrane and carboxyl-terminal domains of the receptors.[38]
- Anandamide
- α-Bungarotoxin
- α-Conotoxin ArIB[V11L,V16D]: potent and highly subtype-selective; slowly reversible[39]
- β-Caryophyllene[40]
- Bupropion (very weakly)
- Dehydronorketamine
- Ethanol
- Hydroxybupropion (very weakly)
- Hydroxynorketamine
- Ketamine
- Kynurenic acid
- Memantine
- Lobeline
- Methyllycaconitine[20]
- Norketamine
- Quinolizidine (–)-1-epi-207I: α7 subtype preferring blocker[41]
See also
- α3β2-Nicotinic receptor
- α3β4-Nicotinic receptor
- α4β2-Nicotinic receptor
- RIC3, a chaperone protein for α7 receptors
- Endocannabinoids
References
- ↑ 1.0 1.1 Pharmacology, (Rang, Dale, Ritter & Moore, ISBN:0-443-07145-4, 5th ed., Churchill Livingstone 2003) p. 138.
- ↑ "Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist". Neuroscience 346: 437–446. March 2017. doi:10.1016/j.neuroscience.2017.01.029. PMID 28147247.
- ↑ "Distribution of neuronal nicotinic acetylcholine receptors containing different alpha-subunits in the submucosal plexus of the guinea-pig". Autonomic Neuroscience 110 (1): 19–26. January 2004. doi:10.1016/j.autneu.2003.08.012. PMID 14766321.
- ↑ "Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit". Science 334 (6052): 98–101. October 2011. doi:10.1126/science.1209985. PMID 21921156. Bibcode: 2011Sci...334...98R.
- ↑ "Physiology and immunology of the cholinergic antiinflammatory pathway". The Journal of Clinical Investigation 117 (2): 289–96. February 2007. doi:10.1172/JCI30555. PMID 17273548.
- ↑ "Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic α7 nicotinic receptors". The Journal of Neuroscience 31 (9): 3446–52. March 2011. doi:10.1523/JNEUROSCI.4558-10.2011. PMID 21368056.
- ↑ "Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia". Archives of General Psychiatry 63 (6): 630–8. June 2006. doi:10.1001/archpsyc.63.6.630. PMID 16754836.
- ↑ Wang, Chen; Chen, Han; Zhu, Wei; Xu, Yinchuan; Liu, Mingfei; Zhu, Lianlian; Yang, Fan; Zhang, Ling et al. (January 2017). "Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells". Arteriosclerosis, Thrombosis, and Vascular Biology 37 (1): 53–65. doi:10.1161/ATVBAHA.116.307264. ISSN 1524-4636. PMID 27834689.
- ↑ "Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization". Psychopharmacology 184 (3–4): 523–39. March 2006. doi:10.1007/s00213-005-0164-7. PMID 16220335.
- ↑ "Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines". International Journal of Cancer 124 (1): 36–45. January 2009. doi:10.1002/ijc.23894. PMID 18844224.
- ↑ "MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway". Angiogenesis 15 (1): 99–114. March 2012. doi:10.1007/s10456-011-9246-9. PMID 22198237.
- ↑ "Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone". Translational Stroke Research 8 (5): 484–493. May 2017. doi:10.1007/s12975-017-0541-7. PMID 28551702.
- ↑ "Mitochondria express α7 nicotinic acetylcholine receptors to regulate Ca2+ accumulation and cytochrome c release: study on isolated mitochondria". PLOS ONE 7 (2): e31361. 2012. doi:10.1371/journal.pone.0031361. PMID 22359587. Bibcode: 2012PLoSO...731361G.
- ↑ "2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands". Bioorganic & Medicinal Chemistry Letters 15 (8): 2073–7. April 2005. doi:10.1016/j.bmcl.2005.02.045. PMID 15808471.
- ↑ "Preclinical characterization of A-582941: a novel alpha7 neuronal nicotinic receptor agonist with broad spectrum cognition-enhancing properties". CNS Neuroscience & Therapeutics 14 (1): 65–82. 2008. doi:10.1111/j.1527-3458.2008.00037.x. PMID 18482100.
- ↑ "Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss". Proceedings of the National Academy of Sciences of the United States of America 110 (27): E2518–27. July 2013. doi:10.1073/pnas.1306832110. PMID 23776240. Bibcode: 2013PNAS..110E2518T.
- ↑ "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". The Journal of Pharmacology and Experimental Therapeutics 309 (1): 16–27. April 2004. doi:10.1124/jpet.103.061655. PMID 14722323.
- ↑ "Normalizing effects of EVP-6124, an α-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia". Journal of Psychiatric Practice 20 (1): 12–24. January 2014. doi:10.1097/01.pra.0000442935.15833.c5. PMID 24419307.
- ↑ "Archived copy". http://envivopharma.com/pdf/EVP-6124AAICPressConf.pdf.
- ↑ 20.0 20.1 "Selective activation of α7 nicotinic acetylcholine receptor by PHA-543613 improves Aβ25-35-mediated cognitive deficits in mice". Neuroscience 298: 81–93. July 2015. doi:10.1016/j.neuroscience.2015.04.017. PMID 25881725.
- ↑ "Differential effects of α7 nicotinic receptor agonist PHA-543613 on spatial memory performance of rats in two distinct pharmacological dementia models". Behavioural Brain Research 278: 404–10. February 2015. doi:10.1016/j.bbr.2014.10.030. PMID 25447295.
- ↑ "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". Bioorganic & Medicinal Chemistry Letters 18 (12): 3611–5. June 2008. doi:10.1016/j.bmcl.2008.04.070. PMID 18490160.
- ↑ "Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists". Bioorganic & Medicinal Chemistry 14 (24): 8219–48. December 2006. doi:10.1016/j.bmc.2006.09.019. PMID 17011782.
- ↑ "SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile". Neuropsychopharmacology 32 (1): 1–16. January 2007. doi:10.1038/sj.npp.1301189. PMID 17019409.
- ↑ "The 5-HT3 antagonist tropisetron (ICS 205-930) is a potent and selective alpha7 nicotinic receptor partial agonist". Bioorganic & Medicinal Chemistry Letters 11 (3): 319–21. February 2001. doi:10.1016/S0960-894X(00)00670-3. PMID 11212100.
- ↑ "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): 543–51. July 2012. doi:10.1002/chir.22052. PMID 22566097.
- ↑ González-Rubio, Juana M; Rojo, Jonathan; Tapia, Laura; Maneu, Victoria; Mulet, José; Valor, Luis M.; Criado, Manuel; Sala, Francisco et al. (2004). Borges, R.. ed. Choline as a tool to evaluate nicotinic receptor function in chromaffin cells.. Luis Gandía. Spain: Instituto Teófilo Hernando. https://isccb12.webs.ull.es/PDF-Final/38-Rubio.pdf.
- ↑ "Design, synthesis, and pharmacological characterization of novel spirocyclic quinuclidinyl-Δ2-isoxazoline derivatives as potent and selective agonists of α7 nicotinic acetylcholine receptors". ChemMedChem 6 (5): 889–903. May 2011. doi:10.1002/cmdc.201000514. PMID 21365765.
- ↑ "Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes". Molecular Pharmacology 72 (3): 715–24. September 2007. doi:10.1124/mol.107.035410. PMID 17565004.
- ↑ "A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization". The Journal of Neuroscience 25 (17): 4396–405. April 2005. doi:10.1523/JNEUROSCI.5269-04.2005. PMID 15858066.
- ↑ "An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo". The Journal of Pharmacology and Experimental Therapeutics 323 (1): 294–307. October 2007. doi:10.1124/jpet.107.120436. PMID 17625074.
- ↑ "Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators". Proceedings of the National Academy of Sciences of the United States of America 104 (19): 8059–64. May 2007. doi:10.1073/pnas.0701321104. PMID 17470817. Bibcode: 2007PNAS..104.8059N.
- ↑ "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". Journal of Medicinal Chemistry 52 (10): 3377–84. May 2009. doi:10.1021/jm9003818. PMID 19419141.
- ↑ "In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile". The Journal of Pharmacology and Experimental Therapeutics 330 (1): 257–67. July 2009. doi:10.1124/jpet.109.151886. PMID 19389923.
- ↑ "The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors". Brain Research. Molecular Brain Research 80 (1): 53–62. August 2000. doi:10.1016/S0169-328X(00)00117-0. PMID 11039729.
- ↑ "Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons". Molecular Pharmacology 59 (4): 674–83. April 2001. doi:10.1124/mol.59.4.674. PMID 11259610.
- ↑ "Presynaptic nicotinic acetylcholine receptors as a functional target of nefiracetam in inducing a long-lasting facilitation of hippocampal neurotransmission". Alzheimer Disease and Associated Disorders 14 (Suppl 1): S82–94. 2000. doi:10.1097/00002093-200000001-00013. PMID 10850735.
- ↑ "Additive effects of endogenous cannabinoid anandamide and ethanol on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes". The Journal of Pharmacology and Experimental Therapeutics 313 (3): 1272–80. June 2005. doi:10.1124/jpet.104.081315. PMID 15687372.
- ↑ "Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist". Biochemistry 46 (22): 6628–38. June 2007. doi:10.1021/bi7004202. PMID 17497892.
- ↑ Sharma, Charu; Al Kaabi, Juma M.; Nurulain, Syed M.; Goyal, Sameer N.; Kamal, Mohammad Amjad; Ojha, Shreesh (2016). "Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise". Current Pharmaceutical Design 22 (21): 3237–3264. doi:10.2174/1381612822666160311115226. ISSN 1873-4286. PMID 26965491.
- ↑ "Alkaloids indolizidine 235B', quinolizidine 1-epi-207I, and the tricyclic 205B are potent and selective noncompetitive inhibitors of nicotinic acetylcholine receptors". Molecular Pharmacology 66 (4): 1061–9. October 2004. doi:10.1124/mol.104.000729. PMID 15258256.
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