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

The Recent work has demonstrated a potential role in reducing inflammatory neurotoxicity in stroke, myocardial infarction, sepsis, and Alzheimer's disease.[4][5][6]

The α7 receptor is highly implicated in the efficacy of Varenicline for smoking cessation therapy significantly more than α4β2 which is responsible for Nicotine's rewarding effects. Upregulation of α7-nAChR's is greatly correlated with a stronger response.[7]

An α7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia.[8]

Activation of α7 nicotinic acetylcholine receptor on mast cells, is a mechanism by which nicotine enhances atherosclerosis.[9]

Both α4β2 and α7 nicotinic receptors appear to be critical for memory, working memory, learning, and attention.[10]

α7-nicotinic receptors also appear to be involved in cancer progression. They have been shown to mediate cancer cell proliferation and metastasis.[11] α7 receptors are also involved in angiogenic and neurogenic activity, and have anti-apoptotic effects.[12][13][14]

Ligands

Agonists

Positive allosteric modulators (PAMs)

At least two types of positive allosteric modulators (PAMs) can be distinguished.[30]

  • PNU-120,596[31]
  • NS-1738: marginal effects on α7 desensitization kinetics; modestly brain-penetrant[32]
  • 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[33] In clinical development for cognitive deficits in schizophrenia.
  • A-867744[34][35]
  • 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.[40]

Negative allosteric modulators (NAMs)

See also

References

  1. ^ Rang, H.P. & Dale, M.M. (2003). Pharmacology. 5th ed. Churchill Livingstone. p. 138. ISBN 0-443-07145-4. OCLC 1171033087
  2. ^ Webster MK, Cooley-Themm CA, Barnett JD, Bach HB, Vainner JM, Webster SE, Linn CL (March 2017). "Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist". Neuroscience. 346: 437–446. doi:10.1016/j.neuroscience.2017.01.029. PMC 5341387. PMID 28147247
  3. ^ Glushakov AV, Voytenko LP, Skok MV, Skok V (January 2004). "Distribution of neuronal nicotinic acetylcholine receptors containing different alpha-subunits in the submucosal plexus of the guinea-pig". Autonomic Neuroscience. 110 (1): 19–26. doi:10.1016/j.autneu.2003.08.012. PMID 14766321
  4. ^ Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ (October 2011). "Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit". Science. 334 (6052): 98–101. Bibcode:2011Sci...334...98R. doi:10.1126/science.1209985. PMC 4548937. PMID 21921156
  5. ^ Tracey KJ (February 2007). "Physiology and immunology of the cholinergic antiinflammatory pathway". The Journal of Clinical Investigation. 117 (2): 289–96. doi:10.1172/JCI30555. PMC 1783813. PMID 17273548
  6. ^ Norman GJ, Morris JS, Karelina K, Weil ZM, Zhang N, Al-Abed Y, Brothers HM, Wenk GL, Pavlov VA, Tracey KJ, Devries AC (March 2011). "Cardiopulmonary arrest and resuscitation disrupts cholinergic anti-inflammatory processes: a role for cholinergic α7 nicotinic receptors". The Journal of Neuroscience. 31 (9): 3446–52. doi:10.1523/JNEUROSCI.4558-10.2011. PMC 3758544. PMID 21368056
  7. ^ Santos, J. R.; Tomaz, P. R.; Scholz, J. R.; Gaya, P. V.; Abe, T. O.; Krieger, J. E.; Pereira, A. C.; Santos, P. C. (2020). "Profile of the Nicotinic Cholinergic Receptor Alpha 7 Subunit Gene Expression is Associated with Response to Varenicline Treatment". Genes. 11 (7): 746. doi:10.3390/genes11070746. PMC 7397196. PMID 32640505
  8. ^ Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R (June 2006). "Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia". Archives of General Psychiatry. 63 (6): 630–8. doi:10.1001/archpsyc.63.6.630. PMID 16754836
  9. ^ Wang, Chen; Chen, Han; Zhu, Wei; Xu, Yinchuan; Liu, Mingfei; Zhu, Lianlian; Yang, Fan; Zhang, Ling; Liu, Xianbao (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. PMID 27834689
  10. ^ Levin ED, McClernon FJ, Rezvani AH (March 2006). "Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization". Psychopharmacology. 184 (3–4): 523–39. doi:10.1007/s00213-005-0164-7. PMID 16220335
  11. ^ Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, Banerjee S, Carless M, Kim E, Coppola D, Haura E, Chellappan S (January 2009). "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. doi:10.1002/ijc.23894. PMC 2826200. PMID 18844224
  12. ^ Brown KC, Lau JK, Dom AM, Witte TR, Luo H, Crabtree CM, Shah YH, Shiflett BS, Marcelo AJ, Proper NA, Hardman WE, Egleton RD, Chen YC, Mangiarua EI, Dasgupta P (March 2012). "MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway". Angiogenesis. 15 (1): 99–114. doi:10.1007/s10456-011-9246-9. PMID 22198237
  13. ^ Wang J, Lu Z, Fu X, Zhang D, Yu L, Li N, Gao Y, Liu X, Yin C, Ke J, Li L, Zhai M, Wu S, Fan J, Lv L, Liu J, Chen X, Yang Q, Wang J (May 2017). "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. doi:10.1007/s12975-017-0541-7. PMC 5704989. PMID 28551702
  14. ^ Gergalova G, Lykhmus O, Kalashnyk O, Koval L, Chernyshov V, Kryukova E, Tsetlin V, Komisarenko S, Skok M (2012). "Mitochondria express α7 nicotinic acetylcholine receptors to regulate Ca2+ accumulation and cytochrome c release: study on isolated mitochondria". PLOS ONE. 7 (2). Bibcode:2012PLoSO...731361G. doi:10.1371/journal.pone.0031361. PMC 3281078. PMID 22359587
  15. ^ Mazurov A, Klucik J, Miao L, Phillips TY, Seamans A, Schmitt JD, Hauser TA, Johnson RT, Miller C (April 2005). "2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands". Bioorganic & Medicinal Chemistry Letters. 15 (8): 2073–7. doi:10.1016/j.bmcl.2005.02.045. PMID 15808471
  16. ^ Tietje KR, Anderson DJ, Bitner RS, Blomme EA, Brackemeyer PJ, Briggs CA, Browman KE, Bury D, Curzon P, Drescher KU, Frost JM, Fryer RM, Fox GB, Gronlien JH, Håkerud M, Gubbins EJ, Halm S, Harris R, Helfrich RJ, Kohlhaas KL, Law D, Malysz J, Marsh KC, Martin RL, Meyer MD, Molesky AL, Nikkel AL, Otte S, Pan L, Puttfarcken PS, Radek RJ, Robb HM, Spies E, Thorin-Hagene K, Waring JF, Ween H, Xu H, Gopalakrishnan M, Bunnelle WH (2008). "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. doi:10.1111/j.1527-3458.2008.00037.x. PMC 6494002. PMID 18482100
  17. ^ Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Piña-Crespo JC, Lipton SA (July 2013). "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. Bibcode:2013PNAS..110E2518T. doi:10.1073/pnas.1306832110. PMC 3704025. PMID 23776240
  18. ^ Marrero MB, Papke RL, Bhatti BS, Shaw S, Bencherif M (April 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". The Journal of Pharmacology and Experimental Therapeutics. 309 (1): 16–27. CiteSeerX 10.1.1.420.2457. doi:10.1124/jpet.103.061655. PMID 14722323
  19. ^ Preskorn SH, Gawryl M, Dgetluck N, Palfreyman M, Bauer LO, Hilt DC (January 2014). "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. doi:10.1097/01.pra.0000442935.15833.c5. PMID 24419307
  20. ^ "EVP-6124, A Selective Alpha-7 Partial Agonist, has Positive Effects on Cognition and Clinical Function in Mild to Moderate Alzheimer's Disease Patients: Results of a Six-Month, Double-Blind, Placebo Controlled, Dose Ranging Study". EnVivo Pharmaceuticals. 2012. Archived 2013-03-19 at the Wayback Machine. Retrieved 2014-03-13.
  21. ^ Sadigh-Eteghad S, Talebi M, Mahmoudi J, Babri S, Shanehbandi D (July 2015). "Selective activation of α7 nicotinic acetylcholine receptor by PHA-543613 improves Aβ25-35-mediated cognitive deficits in mice". Neuroscience. 298: 81–93. doi:10.1016/j.neuroscience.2015.04.017. PMID 25881725
  22. ^ Bali ZK, Inkeller J, Csurgyók R, Bruszt N, Horváth H, Hernádi I (February 2015). "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. doi:10.1016/j.bbr.2014.10.030. PMID 25447295
  23. ^ Acker, Brad A.; Jacobsen, E. Jon; Rogers, Bruce N.; Wishka, Donn G.; Reitz, Steven C.; Piotrowski, David W.; Myers, Jason K.; Wolfe, Mark L.; Groppi, Vincent E.; Thornburgh, Bruce A.; Tinholt, Paula M.; Walters, Rodney R.; Olson, Barbara A.; Fitzgerald, Laura; Staton, Brian A.; Raub, Thomas J.; Krause, Michael; Li, Kai S.; Hoffmann, William E.; Hajos, Mihaly; Hurst, Raymond S.; Walker, Daniel P. (June 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 α7 nicotinic acetylcholine receptor: In vitro and in vivo activity". Bioorganic & Medicinal Chemistry Letters. 18 (12): 3611–3615. doi:10.1016/j.bmcl.2008.04.070. PMID 18490160
  24. ^ Walker DP, Wishka DG, Piotrowski DW, Jia S, Reitz SC, Yates KM, Myers JK, Vetman TN, Margolis BJ, Jacobsen EJ, Acker BA, Groppi VE, Wolfe ML, Thornburgh BA, Tinholt PM, Cortes-Burgos LA, Walters RR, Hester MR, Seest EP, Dolak LA, Han F, Olson BA, Fitzgerald L, Staton BA, Raub TJ, Hajos M, Hoffmann WE, Li KS, Higdon NR, Wall TM, Hurst RS, Wong EH, Rogers BN (December 2006). "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. doi:10.1016/j.bmc.2006.09.019. PMID 17011782
  25. ^ Biton B, Bergis OE, Galli F, Nedelec A, Lochead AW, Jegham S, Godet D, Lanneau C, Santamaria R, Chesney F, Léonardon J, Granger P, Debono MW, Bohme GA, Sgard F, Besnard F, Graham D, Coste A, Oblin A, Curet O, Vigé X, Voltz C, Rouquier L, Souilhac J, Santucci V, Gueudet C, Françon D, Steinberg R, Griebel G, Oury-Donat F, George P, Avenet P, Scatton B (January 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
  26. ^ Macor JE, Gurley D, Lanthorn T, Loch J, Mack RA, Mullen G, Tran O, Wright N, Gordon JC (February 2001). "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. doi:10.1016/S0960-894X(00)00670-3. PMID 11212100
  27. ^ Dallanoce C, Matera C, De Amici M, Rizzi L, Pucci L, Gotti C, Clementi F, De Micheli C (July 2012). "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. doi:10.1002/chir.22052. PMID 22566097
  28. ^ González-Rubio, Juana Mª; Rojo, Jonathan; Tapia López, Laura; Maneu Flores, Victoria; Mulet, José; Valor, Luis M.; Criado, Manuel; Sala, Francisco; García, Antonio G.; Gandía Juan, Luis (2004). "Choline as a tool to evaluate nicotinic receptor function in chromaffin cells". Cell Biology of the Chromaffin Cell. pp. 255–260. ISBN 84-688-7007-2.
  29. ^ Dallanoce C, Magrone P, Matera C, Frigerio F, Grazioso G, De Amici M, Fucile S, Piccari V, Frydenvang K, Pucci L, Gotti C, Clementi F, De Micheli C (May 2011). "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. doi:10.1002/cmdc.201000514. PMID 21365765
  30. ^ Grønlien JH, Håkerud M, Ween H, Thorin-Hagene K, Briggs CA, Gopalakrishnan M, Malysz J (September 2007). "Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes". Molecular Pharmacology. 72 (3): 715–24. doi:10.1124/mol.107.035410. PMID 17565004
  31. ^ Hurst RS, Hajós M, Raggenbass M, Wall TM, Higdon NR, Lawson JA, Rutherford-Root KL, Berkenpas MB, Hoffmann WE, Piotrowski DW, Groppi VE, Allaman G, Ogier R, Bertrand S, Bertrand D, Arneric SP (April 2005). "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. doi:10.1523/JNEUROSCI.5269-04.2005. PMC 6725110. PMID 15858066
  32. ^ Timmermann DB, Grønlien JH, Kohlhaas KL, Nielsen EØ, Dam E, Jørgensen TD, Ahring PK, Peters D, Holst D, Christensen JK, Malysz J, Briggs CA, Gopalakrishnan M, Olsen GM (October 2007). "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. doi:10.1124/jpet.107.120436. PMID 17625074
  33. ^ Ng HJ, Whittemore ER, Tran MB, Hogenkamp DJ, Broide RS, Johnstone TB, Zheng L, Stevens KE, Gee KW (May 2007). "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. Bibcode:2007PNAS..104.8059N. doi:10.1073/pnas.0701321104. PMC 1876571. PMID 17470817
  34. ^ Faghih R, Gopalakrishnan SM, Gronlien JH, Malysz J, Briggs CA, Wetterstrand C, Ween H, Curtis MP, Sarris KA, Gfesser GA, El-Kouhen R, Robb HM, Radek RJ, Marsh KC, Bunnelle WH, Gopalakrishnan M (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". Journal of Medicinal Chemistry. 52 (10): 3377–84. doi:10.1021/jm9003818. PMID 19419141
  35. ^ Malysz J, Grønlien JH, Anderson DJ, Håkerud M, Thorin-Hagene K, Ween H, Wetterstrand C, Briggs CA, Faghih R, Bunnelle WH, Gopalakrishnan M (July 2009). "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. doi:10.1124/jpet.109.151886. PMID 19389923
  36. ^ Nishizaki T, Nomura T, Matuoka T, Kondoh T, Enikolopov G, Enikolopo G, Sumikawa K, Watabe S, Shiotani T, Yoshii M (August 2000). "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. doi:10.1016/S0169-328X(00)00117-0. PMID 11039729
  37. ^ Zhao X, Kuryatov A, Lindstrom JM, Yeh JZ, Narahashi T (April 2001). "Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons". Molecular Pharmacology. 59 (4): 674–83. doi:10.1124/mol.59.4.674. PMID 11259610
  38. ^ Nishizaki T, Matsuoka T, Nomura T, Kondoh T, Watabe S, Shiotani T, Yoshii M (2000). "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. doi:10.1097/00002093-200000001-00013. PMID 10850735
  39. ^ Pan, Zhi-Yuan & Wang, Hai (May 2014). "Synergistic interaction between choline and aspirin against acute inflammation induced by carrageenan and lipopolysaccharide". International Immunopharmacology. 20 (1): 229–237. doi:10.1016/j.intimp.2014.03.004. PMID 24656779
  40. ^ Oz M, Jackson SN, Woods AS, Morales M, Zhang L (June 2005). "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. doi:10.1124/jpet.104.081315. PMID 15687372
  41. ^ Whiteaker P, Christensen S, Yoshikami D, Dowell C, Watkins M, Gulyas J, Rivier J, Olivera BM, McIntosh JM (June 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
  42. ^ 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): 3237–64. doi:10.2174/1381612822666160311115226. PMID 26965491
  43. ^ Garton DR, Ross SG, Maldonado-Hernández R, Quick M, Lasalde-Dominicci JA, Lizardi-Ortiz JE (2019). "Amphetamine enantiomers inhibit homomeric α7 nicotinic receptor through a competitive mechanism and within the intoxication levels in humans". Neuropharmacology. 144: 172–183. doi:10.1016/j.neuropharm.2018.10.032. PMC 6286198. PMID 30359640
  44. ^ Tsuneki H, You Y, Toyooka N, Kagawa S, Kobayashi S, Sasaoka T, Nemoto H, Kimura I, Dani JA (October 2004). "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. doi:10.1124/mol.104.000729. PMID 15258256
  45. ^ Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, Rosenberg A, Tran T, Xiao Y, Zarate CA, Wainer IW (January 2013). "Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors". Eur J Pharmacol. 698 (1–3): 228–34. doi:10.1016/j.ejphar.2012.11.023. PMC 3534778. PMID 23183107