GPCRs as Targets for Plant-Derived Drugs

  • Angelika BöttgerEmail author
  • Ute Vothknecht
  • Cordelia Bolle
  • Alexander Wolf
Part of the Learning Materials in Biosciences book series (LMB)


The family of GPCRs represents the most important class of pharmaceutical drug targets. In this chapter, we describe such receptors and pathways that are targets for well-known plant-derived drugs and toxins. These include adrenergic receptors, the muscarinic acetylcholine receptor (MAchR), adenosine receptors, cannabinoid receptors, dopamine- and serotonin (5HT) receptors/transporters and opiate receptors. They are targets for compounds such as cannabis, muscarine and atropine, caffeine, cocaine, morphine and hallucinogenic drugs, among others.


  1. Alagha K, Palot A, Sofalvi T, Pahus L, Gouitaa M, Tummino C, Martinez S, Charpin D, Bourdin A, Chanez P (2014) Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases. Ther Adv Chronic Dis 5:85–98CrossRefGoogle Scholar
  2. Barnes PJ (2013) Theophylline. Am J Respir Crit Care Med 188:901–906CrossRefGoogle Scholar
  3. Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63:182–217CrossRefGoogle Scholar
  4. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 6:237–249CrossRefGoogle Scholar
  5. Borea PA, Varani K, Vincenzi F, Baraldi PG, Tabrizi MA, Merighi S, Gessi S (2015) The A3 adenosine receptor: history and perspectives. Pharmacol Rev 67:74–102CrossRefGoogle Scholar
  6. Boyd KN, Mailman RB (2012) Dopamine receptor signaling and current and future antipsychotic drugs. Handb Exp Pharmacol 212:53–86Google Scholar
  7. Brown SP, Safo PK, Regehr WG (2004) Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels. J Neurosci 24:5623–5631CrossRefGoogle Scholar
  8. Catterall WA (2015) Regulation of cardiac calcium channels in the fight-or-flight response. Curr Mol Pharmacol 8:12–21CrossRefGoogle Scholar
  9. Cross SA (1994) Pathophysiology of pain. Mayo Clin Proc 69:375–383CrossRefGoogle Scholar
  10. Dalton GD, Bass CE, Van Horn CG, Howlett AC (2009) Signal transduction via cannabinoid receptors. CNS Neurol Disord Drug Targets 8:422–431CrossRefGoogle Scholar
  11. Davis RL, Cherry J, Dauwalder B, Han PL, Skoulakis E (1995) The cyclic AMP system and Drosophila learning. Mol Cell Biochem 149–150:271–278CrossRefGoogle Scholar
  12. de Lera Ruiz M, Lim YH, Zheng J (2014) Adenosine A2A receptor as a drug discovery target. J Med Chem 57:3623–3650CrossRefGoogle Scholar
  13. De Petrocellis L, Nabissi M, Santoni G, Ligresti A (2017) Actions and regulation of ionotropic cannabinoid receptors. Adv Pharmacol 80:249–289CrossRefGoogle Scholar
  14. Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CD (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79CrossRefGoogle Scholar
  15. Eiden LE, Weihe E (2011) VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci 1216:86–98CrossRefGoogle Scholar
  16. Fergus IV, Connell KL, Ferdinand KC (2015) A comparison of vasodilating and non-VASODILATING beta-blockers and their effects on cardiometabolic risk. Curr Cardiol Rep 17:38CrossRefGoogle Scholar
  17. Ferre S (2010) Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine. J Alzheimer’s Dis: JAD 20(Suppl 1):S35–S49CrossRefGoogle Scholar
  18. Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD Jr, Brezina V, Sealfon SC, Filizola M, Gonzalez-Maeso J, Logothetis DE (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011–1023CrossRefGoogle Scholar
  19. Hoffer A (1967) A program for the treatment of alcoholism: LSD, malvaria and nicotinic acid. In: Abramson HA (ed) The use of LSD in psychotherapy and alcoholism. Bobbs-Merrill, Indianapolis, pp 343–406Google Scholar
  20. Hokfelt T (2010) Looking at neurotransmitters in the microscope. Prog Neurobiol 90:101–118CrossRefGoogle Scholar
  21. Huang ZL, Urade Y, Hayaishi O (2011) The role of adenosine in the regulation of sleep. Curr Top Med Chem 11:1047–1057CrossRefGoogle Scholar
  22. Johnson KA, Lovinger DM (2016) Presynaptic G protein-coupled receptors: gatekeepers of addiction? Front Cell Neurosci 10:264CrossRefGoogle Scholar
  23. Kivell BM, Ewald AW, Prisinzano TE (2014) Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. Adv Pharmacol 69:481–511CrossRefGoogle Scholar
  24. Kobayashi S, Endou M, Sakuraya F, Matsuda N, Zhang XH, Azuma M, Echigo N, Kemmotsu O, Hattori Y, Gando S (2003) The sympathomimetic actions of l-ephedrine and d-pseudoephedrine: direct receptor activation or norepinephrine release? Anesth Analg 97:1239–1245CrossRefGoogle Scholar
  25. Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hubner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK (2013) Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature 504:101–106CrossRefGoogle Scholar
  26. Kruse AC, Kobilka BK, Gautam D, Sexton PM, Christopoulos A, Wess J (2014) Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov 13:549–560CrossRefGoogle Scholar
  27. Landolt HP (2008) Sleep homeostasis: a role for adenosine in humans? Biochem Pharmacol 75:2070–2079CrossRefGoogle Scholar
  28. Lemieux G, Davignon A, Genest J (1956) Depressive states during Rauwolfia therapy for arterial hypertension; a report of 30 cases. Can Med Assoc J 74:522–526PubMedPubMedCentralGoogle Scholar
  29. Lewin L (1964) Phantastica, narcotic, and stimulating drugs. their use and abuse. Routledge, LondonGoogle Scholar
  30. Ma G, Bavadekar SA, Davis YM, Lalchandani SG, Nagmani R, Schaneberg BT, Khan IA, Feller DR (2007) Pharmacological effects of ephedrine alkaloids on human alpha(1)- and alpha(2)-adrenergic receptor subtypes. J Pharmacol Exp Ther 322:214–221CrossRefGoogle Scholar
  31. Mackie K (2005) Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol 168:299–325Google Scholar
  32. Melancon BJ, Tarr JC, Panarese JD, Wood MR, Lindsley CW (2013) Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer’s disease. Drug Discov Today 18:1185–1199CrossRefGoogle Scholar
  33. Merighi A, Salio C, Ferrini F, Lossi L (2011) Neuromodulatory function of neuropeptides in the normal CNS. J Chem Neuroanat 42:276–287CrossRefGoogle Scholar
  34. Mustard JA (2014) The buzz on caffeine in invertebrates: effects on behavior and molecular mechanisms. Cell Mol Life Sci: CMLS 71:1375–1382CrossRefGoogle Scholar
  35. Nehlig A, Armspach JP, Namer IJ (2010) SPECT assessment of brain activation induced by caffeine: no effect on areas involved in dependence. Dialogues Clin Neurosci 12:255–263PubMedPubMedCentralGoogle Scholar
  36. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181CrossRefGoogle Scholar
  37. Nickalls RW, Nickalls EA (1988) The first use of physostigmine in the treatment of atropine poisoning. A translation of Kleinwachter’s paper entitled 'Observations on the effect of Calabar bean extract as an antidote to atropine poisoning. Anaesthesia 43:776–779CrossRefGoogle Scholar
  38. Nyiri G, Cserep C, Szabadits E, Mackie K, Freund TF (2005) CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons. Neuroscience 136:811–822CrossRefGoogle Scholar
  39. Ogrodowczyk M, Dettlaff K, Jelinska A (2016) Beta-blockers: current state of knowledge and perspectives. Mini Rev Med Chem 16:40–54CrossRefGoogle Scholar
  40. Ohno-Shosaku T, Tanimura A, Hashimotodani Y, Kano M (2012) Endocannabinoids and retrograde modulation of synaptic transmission. Neuroscientist 18:119–132CrossRefGoogle Scholar
  41. Osmond H, Smythies J (1952) Schizophrenia: a new approach. J Ment Sci 98:309–315CrossRefGoogle Scholar
  42. Pasternak GW, Pan YX (2013) Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 65:1257–1317CrossRefGoogle Scholar
  43. Paul K, Ruck CA, Bigwood J, Staples D, Ott J, Wasson RG (1979) Entheogens. J Psychedelic Drugs 11:145–146CrossRefGoogle Scholar
  44. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedGoogle Scholar
  45. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215CrossRefGoogle Scholar
  46. Pessah IN, Stambuk RA, Casida JE (1987) Ca2+−activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg2+, caffeine, and adenine nucleotides. Mol Pharmacol 31:232–238PubMedGoogle Scholar
  47. Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450:383–387CrossRefGoogle Scholar
  48. Rivera-Oliver M, Diaz-Rios M (2014) Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life Sci 101:1–9CrossRefGoogle Scholar
  49. Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA (2003) In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther 307:138–145CrossRefGoogle Scholar
  50. Seeman P (2014) Clozapine, a fast-off-D2 antipsychotic. ACS Chem Neurosci 5:24–29CrossRefGoogle Scholar
  51. Shamon SD, Perez MI (2009) Blood pressure lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev:CD007655Google Scholar
  52. Shannon M, Neuman MI (2000) Yohimbine. Pediatr Emerg Care 16:49–50CrossRefGoogle Scholar
  53. Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dube S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC (2008) Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry 165:1033–1039CrossRefGoogle Scholar
  54. Simonson B, Morani AS, Ewald AW, Walker L, Kumar N, Simpson D, Miller JH, Prisinzano TE, Kivell BM (2015) Pharmacology and anti-addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. Br J Pharmacol 172:515–531CrossRefGoogle Scholar
  55. Stacy M, Silver D (2008) Apomorphine for the acute treatment of "off" episodes in Parkinson's disease. Parkinsonism Relat Disord 14:85–92CrossRefGoogle Scholar
  56. Thiele A (2013) Muscarinic signaling in the brain. Annu Rev Neurosci 36:271–294CrossRefGoogle Scholar
  57. Tso PH, Wong YH (2003) Molecular basis of opioid dependence: role of signal regulation by G-proteins. Clin Exp Pharmacol Physiol 30:307–316CrossRefGoogle Scholar
  58. Ulugol A (2014) The endocannabinoid system as a potential therapeutic target for pain modulation. Balkan Med J 31:115–120CrossRefGoogle Scholar
  59. Vansal SS, Feller DR (1999) Direct effects of ephedrine isomers on human beta-adrenergic receptor subtypes. Biochem Pharmacol 58:807–810CrossRefGoogle Scholar
  60. Vaughan RA, Foster JD (2013) Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci 34:489–496CrossRefGoogle Scholar
  61. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592CrossRefGoogle Scholar
  62. Yeh B (2012) The controlled substances act: regulatory requirements. Congressional Res Serv:1–17Google Scholar
  63. Zajdel P, Bednarski M, Sapa J, Nowak G (2015) Ergotamine and nicergoline - facts and myths. Pharmacol Rep: PR 67:360–363CrossRefGoogle Scholar
  64. Zhang N, Lian Z, Peng X, Li Z, Zhu H (2017) Applications of higenamine in pharmacology and medicine. J Ethnopharmacol 196:242–252CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Angelika Böttger
    • 1
    Email author
  • Ute Vothknecht
    • 2
  • Cordelia Bolle
    • 3
  • Alexander Wolf
    • 4
  1. 1.Department Biology IILMU MunichPlanegg-MartinsriedGermany
  2. 2.IZMB-Plant Cell BiologyUniversity of BonnBonnGermany
  3. 3.Department Biology ILMU MunichPlanegg-MartinsriedGermany
  4. 4.Inst. Molecular Toxicology/PharmacologyHelmholtz Zentrum MünichNeuherbergGermany

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