Allosteric modulators of cannabinoid receptors hold great therapeutic potential, as they do not possess intrinsic efficacy, but instead enhance or diminish the receptor's response of orthosteric ligands allowing for the tempering of cannabinoid receptor signaling without the desensitization, tolerance and dependence. Allosteric modulators of cannabinoid receptors have numerous advantages over the orthosteric ligands such as higher receptor type selectivity, probe dependence and biased signaling, so they have a great potential to separate the therapeutic benefits from side effects own of orthosteric ligands. This review aims to give an overview of the CB1 and CB2 receptor allosteric modulators highlighting the structure–activity relationship and pharmacological profile of each classes, and their future promise.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat. Rev. Drug Discov. 17(9), 623–639 (2018).
MedlineGoogle Scholar
2. Piomelli D. More surprises lying ahead. The endocannabinoids keep us guessing. Neuropharmacology 76(Pt B), 228–234 (2014).
Medline CASGoogle Scholar
3. Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH. Cannabinoid receptor-related orphan G protein-coupled receptors. Adv. Pharmacol. 80, 223–247 (2017).
Medline CASGoogle Scholar
4. Kaur R, Ambwani SR, Singh S. Endocannabinoid system: a multi-facet therapeutic target. Curr. Clin. Pharmacol. 11(2), 110–117 (2016).
Medline CASGoogle Scholar
5. Navarro G, Morales P, Rodríguez-Cueto C, Fernández-Ruiz J, Jagerovic N, Franco R. Targeting cannabinoid CB2 receptors in the central nervous system. medicinal chemistry approaches with focus on neurodegenerative disorders. Front. Neurosci. 10, 406 (2016).
MedlineGoogle Scholar
6. Picone RP, Kendall D. Minireview: from the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation. Mol. Endocrinol. 29(6), 801–813 (2015).
Medline CASGoogle Scholar
7. Kendall DA, Yudowski GA. Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Front. Cell. Neurosci. 10, 1–10 (2017).
Google Scholar
8. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc. B: Biol. Sci. 367(1607), 3353–3363 (2012).
Medline CASGoogle Scholar
9. Howlett AC, Abood ME. CB1 and CB2 receptor pharmacology. Adv Pharmacol. 80, 169–206 (2017).
Medline CASGoogle Scholar
10. Manera C, Arena C, Chicca A. Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders. Recent Pat. CNS Drug Discov. 10(2), 142–156 (2016).
MedlineGoogle Scholar
11. Richey JM, Woolcott O. Re-visiting the endocannabinoid system and its therapeutic potential in obesity and associated diseases. Curr Diab. Rep. 17(10), 99 (2017).
MedlineGoogle Scholar
12. Ibarra-Lecue I, Pilar-Cuéllar F, Muguruza C et al. The endocannabinoid system in mental disorders: evidence from human brain studies. Biochem. Pharmacol. 157, 97–107 (2018).
Medline CASGoogle Scholar
13. Poleszak E, Wośko S, Sławińska K, Szopa A, Wróbel A, Serefko A. Cannabinoids in depressive disorders. Life Sci. 213, 18–24 (2018).
Medline CASGoogle Scholar
14. Lötsch J, Weyer-Menkhoff I, Tegeder I. Current evidence of cannabinoid-based analgesia obtained in preclinical and human experimental settings. Eur. J. Pain 22, 471–484 (2018).
Medline CASGoogle Scholar
15. Donvito G, Nass SR, Wilkerson JL et al. The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmacology 43, 52–79 (2018).
Medline CASGoogle Scholar
16. Chiurchiù V, van der Stelt M, Centonze D, Maccarrone M. The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases. Prog. Neurobiol. 160, 82–100 (2018).
Medline CASGoogle Scholar
17. Gado F, Digiacomo M, Macchia M, Bertini S, Manera C. Traditional uses of cannabinoids and new perspectives in the treatment of multiple sclerosis. Medicines (Basel) 5(3), 91 (2018).
CASGoogle Scholar
18. Manzanaresa J, Cabañero D, Puentec N, García-Gutiérreza MS, Grandesc P, Maldonado R. Role of the endocannabinoid system in drug addiction. Biochem. Pharmacol. 157, 108–121 (2018).
MedlineGoogle Scholar
19. He XH, Chloe Jordan CJ, Vemuri K et al. Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats. Acta Pharmacol. Sin. 40(3), 365–373 (2019).
Medline CASGoogle Scholar
20. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 33, 195–209 (2013).
Medline CASGoogle Scholar
21. Cassano T, Calcagnini S, Pace L, De Marco F, Romano A, Gaetani S. Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Front. Neurosci. 11, 30 (2017).
MedlineGoogle Scholar
22. Fonseca BM, Teixeira NA, Correia-da-Silva G. Cannabinoids as modulators of cell death: clinical applications and future directions. Rev. Physiol. Biochem. Pharmacol. 173, 63–88 (2017).
Medline CASGoogle Scholar
23. Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiol. 215, 598–605 (2010).
Medline CASGoogle Scholar
24. Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: omplications for drug discovery. Nat. Rev. Drug Discov. 12(8), 630–644 (2013). • Discusses the potential advantages of allosteric ligands and highlights opportunities that arise from these advantages.
Medline CASGoogle Scholar
25. Bartuzi D, Kaczor AA, Matosiuk D. Opportunities and challenges in the discovery of allosteric modulators of GPCRs. Methods Mol. Biol. 1705, 297–319 (2018).
Medline CASGoogle Scholar
26. Shore DM, Baillie G, Hurst DH et al. Allosteric modulation of a cannabinoid G protein-coupled receptor: binding site elucidation and relationship to G protein signaling. J. Biol. Chem. 289(9), 5828–5845 (2014). • Describes the binding site of allosteric modulator ORG27569 at CB1 receptors.
Medline CASGoogle Scholar
27. Stornaiuolo M, Bruno A, Botta L et al. Endogenous vs exogenous allosteric modulators in GPCRs: a dispute for shuttling CB1 among different membrane microenvironments. Sci Rep. 5, 15453 (2015).
Medline CASGoogle Scholar
28. Sabatucci A, Tortolani D, Dainese E, Maccarrone M. In silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor. Biotechnol. Appl. Biochem. 65(1), 21–28 (2018).
Medline CASGoogle Scholar
29. Feng Z, Alqarni MH, Yang P et al. Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J. Chem. Inf. Model. 54(9), 2483–2499 (2014).
Medline CASGoogle Scholar
30. Pandey P, Roy KK, Doerksen RJ. Negative allosteric modulators of cannabinoid receptor 2: protein modeling, binding site identification and molecular dynamics simulations in the presence of an orthosteric agonist. J. Biomol. Struct. Dyn. 5, 1–16 (2019).
Google Scholar
31. Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: A novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8(1), 41–45 (2009).
Medline CASGoogle Scholar
32. Congreve M, Oswald C, Marshall FH. Applying structure-based drug design approaches to allosteric modulators of GPCRs. Trends Pharmacol. Sci. 38(9), 837–847 (2017). • Considers the types of allosteric pockets and the mode of modulation as well as the advantages and disadvantages of targeting allosteric pockets respect to the natural orthosteric site.
Medline CASGoogle Scholar
33. Gentry PR, Sexton PM, Christopoulos A. Novel allosteric modulators of G-protein coupled receptors. J. Biol. Chem. 290, 19478–19488 (2015).
Medline CASGoogle Scholar
34. Burford NT, Clark MJ, Wehrman TS et al. Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor. Proc. Natl Acad. Sci. USA. 110, 10830–10835 (2013).
Medline CASGoogle Scholar
35. Alaverdashvili M, Laprairie RB. The future of type 1 cannabinoid receptor allosteric ligands. Drug Metab. Rev. 50(1), 14–25 (2018).
Medline CASGoogle Scholar
36. Toczek M, Malinowska B. Enhanced endocannabinoid tone as a potential target of pharmacotherapy. Life Sci. 204, 20–45 (2018).
Medline CASGoogle Scholar
37. Greco R, Demartini C, Zanaboni AM, Piomelli D, Tassorelli C. Endocannabinoid System and Migraine Pain: An Update. Front. Neurosci. 12, 172 (2018).
MedlineGoogle Scholar
38. Kenakin T, Miller LJ. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol. Rev. 62, 265–304 (2010).
Medline CASGoogle Scholar
39. Kenakin TP. Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br. J. Pharmacol. 165(6), 1659–1669 (2012).
Medline CASGoogle Scholar
40. Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 17(4), 243–260 (2018). •• Presents recent evidences that biased agonists have the potential to increase clinical efficacy while reducing undesirable side effects.
Medline CASGoogle Scholar
41. Price MR, Baillie GL, Thomas A et al. Allosteric modulation of the cannabinoid CB1 receptor. Mol. Pharmacol. 68(5), 1484–1495 (2005).
Medline CASGoogle Scholar
42. Ahn KH, Mahmoud MM, Kendall DA. Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. J. Biol. Chem. 287(50), 12070–12082 (2012).
Medline CASGoogle Scholar
43. Baillie G, Horswill JG, Anavi-Goffer S et al. CB1 receptor allosteric modulators display both agonist and signaling pathway specifity. Mol. Pharmacol. 83(2), 322–338 (2013).
Medline CASGoogle Scholar
44. Khajehali E, Malone DT, Glass M, Sexton PM, Christopoulos A, Leach K. Biased agonism and biased allosteric modulation at the CB1 receptors. Mol. Pharmacol. 88(2), 368–379 (2015).
Medline CASGoogle Scholar
45. Cawston EE, Redmond WJ, Breen CM, Grimsey NL, Connor M, Glass M. Real-time characterization of cannabinoid receptor 1 (CB1) allosteric modulators reveals novel mechanism of action. Br. J. Pharmacol. 170(4), 893–907 (2013).
Medline CASGoogle Scholar
46. Fay JF, Farrens DL. A key agonist – induced conformational change in the cannabinoid receptor CB1 is blocked by the allosteric ligand Org 27569. J. Biol. Chem. 287(40), 33873–33882 (2012).
Medline CASGoogle Scholar
47. Fay JF, Farrens DL. Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1. Proc Natl Acad Sci USA 112(27), 8469–8479 (2015).
Medline CASGoogle Scholar
48. Ahn KH, Mahmoud MM, Shim JY, Kendall DA. Distinct roles of β-arrestin 1 and β-arrestin 2 in ORG27569-induced biased signaling and internalization of the cannabinoid receptor 1 (CB1). J. Biol. Chem. 288(14), 9790–800 (2013).
Medline CASGoogle Scholar
49. Straiker A, Mitjavila J, Yin D, Gibson A, Mackie K. Aiming for allosterism: evaluation of allosteric modulators of CB1 in a neuronal model. Pharmacol. Res. 99, 370–376 (2015).
Medline CASGoogle Scholar
50. Gamage TF, Ignatowska-Jankowska BM, Wiley JL et al. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav. Pharmacol. 25(2), 182–185 (2014).
Medline CASGoogle Scholar
51. Jing L, Qiu Y, Zhang Y, Li J. Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and –methamphetamine-seeking behaviour in rats. Drug Alcohol Depend. 143, 251–256 (2014).
Medline CASGoogle Scholar
52. Piscitelli F, Ligresti A, La Regina G et al. Indole 2-carboxamides as allosteric modulators of the cannabinoid CB1 receptor. J. Med. Chem. 55(11), 5627–5631 (2012).
Medline CASGoogle Scholar
53. Mahmoud MM, Ali HI, Ahn KH et al. Structure–activity relationship study of Indole-2-carboxamides identifies a potent allosteric modulator for the cannabinoid receptor 1 (CB1). J. Med. Chem. 56(20), 7965–7975 (2013).
Medline CASGoogle Scholar
54. Kulkarni PM, Kulkarni AR, Korde A et al. Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s). J. Med. Chem. 59(1), 44–60 (2016).
Medline CASGoogle Scholar
55. Nguyen T, German N, Decker AM et al. Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators. Bioorg Med Chem. 23(9), 2195–2203 (2015).
Medline CASGoogle Scholar
56. Morales P, Goya P, Jagerovic N, Hernandez-Folgado L. Allosteric modulators of the CB1 cannabinoid receptor: a structural update review. Cannabis and Cannabinoid Res. 1(1), 196–201 (2016).
Google Scholar
57. Khurana L, Ali HI, Olszewska T et al. Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1). J. Med. Chem. 57(7), 3040–3052 (2014).
Medline CASGoogle Scholar
58. Horswill JG, Bali U, Shaaban S et al. PSNCBAM‐1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br. J. Pharmacol. 152(5), 805–814 (2007).
Medline CASGoogle Scholar
59. Gamage TF, Farquhar CE, Lefever TW et al. The great divide: separation between in vitro and in vivo effects of PSNCBAM-based CB₁ receptor allosteric modulators. Neuropharmacology. 125, 365–375 (2017).
Medline CASGoogle Scholar
60. Wang X, Horswill JG, Whalley BJ, Stephens GJ. Effects of the allosteric antagonist 1-(4-Chlorophenyl)-3-[3-(6-pyrrolidin-1-ylpyridin-2-yl)phenyl]urea (PSNCBAM-1) on CB1 receptor modulation in the cerebellum. Mol. Pharmacol. 79(4), 758–767 (2011).
Medline CASGoogle Scholar
61. Nguyen T, German N, Decker AM et al. Novel diarylurea based allosteric modulators of the cannabinoid CB1 receptor: evaluation of importance of 6-pyrrolidinylpyridinyl substitution. J. Med. Chem. 60(17), 7410–7424 (2017).
Medline CASGoogle Scholar
62. German N, Decker AM, Gilmour BP et al. Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure–activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1). J. Med. Chem. 57(18), 7758–7769 (2014).
Medline CASGoogle Scholar
63. Khurana L, Fu B, Duddupudi AL, Liao Y, Immadi SS, Kendall DA, Lu D. Pyrimidinyl biphenylureas: identification of new lead compounds as allosteric modulators of the cannabinoid receptor CB1. J. Med. Chem. 60(3), 1089–1104 (2017).
Medline CASGoogle Scholar
64. Bertini S, Chicca A, Gado F et al. Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor. Bioorg. Med. Chem. 25(24), 6427–6434 (2017).
Medline CASGoogle Scholar
65. Ignatowska-Jankowska BM, Baillie GL, Kinsey S et al. A cannabinoid CB1 receptor-positive allosteric modulator reduces neuropathic pain in the mouse with no psychoactive effects. Neuropsychopharmacology. 40(13), 2948–2959 (2015).
Medline CASGoogle Scholar
66. Mitjavila J, Yin D, Kulkarni PM et al. Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol. Res. 129, 475–481 (2018).
Medline CASGoogle Scholar
67. Saleh N, Hucke O, Montel F et al. Multiple binding sites contribute to the mechanism of the 2-phenylindole mixed orthosteric agonistic and PAM action on the Cannabinoid CB1 receptor. Angew. Chem. Int. Ed. Engl. 57(10), 2580–2585 (2018).
Medline CASGoogle Scholar
68. Trexler KR, Eckard ML, Kinsey SG. CB1 positive allosteric modulation attenuates Δ9-THC withdrawal and NSAID-induced gastric inflammation. Pharmacol. Biochem. Behav. 177, 27–33 (2019).
Medline CASGoogle Scholar
69. Laprairie RB, Kulkarni PM, Deschamps JR et al. Enantiospecific allosteric modulation of cannabinoid 1 receptor. ACS Chem. Neurosci. 8(6), 1188–1203 (2017). •• Reports the first demonstration of enantiomer-selective CB1 receptor positive allosteric modulation.
Medline CASGoogle Scholar
70. Slivicki RA, Xu Z, Kulkarni PM, Pertwee RG, Mackie K, Thakur GA, Hohmann AG. Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological pain without producing tolerance or dependence. Biol. Psychiatry. 84(10), 722–733 (2018).
Medline CASGoogle Scholar
71. Cairns EA, Szczesniak A, Straiker AJ et al. The in vivo effects of the CB1-positive allosteric modulator GAT229 on intraocular pressure in ocular normotensive and hypertensive mice. J. Ocul. Pharmacol. Ther. 33(8), 582 –590 (2017).
Medline CASGoogle Scholar
72. Thakur GA, Kulkarni PM. WO2013103967 (2017).
Google Scholar
73. Ruth R, Greig I, Zanda M, Tseng CC. WO2016029310, (2018).
Google Scholar
74. Gado F, Di Cesare Mannelli L, Lucarini E et al. Identification of the First synthetic allosteric modulator of the CB2 receptors and evidence of its efficacy for neuropathic pain relief. J. Med. Chem. doi: 10.1021/acs.jmedchem.8b00368 (2018) (Epub ahead of print).
MedlineGoogle Scholar
75. Chicca A, Arena C, Bertini S et al. Polypharmacological profile of 1,2-dihydro-2-oxo-pyridine-3-carboxamides in the endocannabinoid system. Eur. J. Med. Chem. 154, 155–171 (2018).
Medline CASGoogle Scholar
76. Morales P, Cascio MG, Stevenson L et al. Pharmacological identification Of Iqm311 as an allosteric modulator of the cannabinoid CB2 receptor. Presented at: 9th Conference on Cannabinoids in Medicine. Cologne, Germany, 29–30 (2017).
Google Scholar
77. Rajasekaran M. Characterization of allosteric modulators of CB2 receptors as novel therapeutics for inflammatory diseases. PhD Thesis, The University of Arkansas for Medical Sciences (2011).
Google Scholar
78. Vallée M, Vitiello S, Bellocchio L et al. Pregnenolone can protect the brain from cannabis intoxication. Science 343, 6166 (2014).
Google Scholar
79. Krohmer A, Brehm M, Auwärter V, Szabo B. Pregnenolone does not interfere with the effects of cannabinoids on synaptic transmission in the cerebellum and the nucleus accumbens. Pharmacol. Res. 123, 51–61 (2017).
Medline CASGoogle Scholar
80. Wang W, Jia Y, Pham DT et al. Atypical Endocannabinoid signaling initiates a new form of memory-related plasticity at a cortical input to hippocampus. Cerebral Cortex 28, 2253–2266 (2018).
MedlineGoogle Scholar
81. Busquets-Garcia A, Soria-Gòmez E, Redon B et al. Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice. Mol. Psychiatry. 22(11), 1594–1603 (2017).
Medline CASGoogle Scholar
82. Zurier RB, Sun Y, George KL et al. Ajulemic acid, a synthetic cannabinoid, increases formation of the endogenous proresolving and anti-inflammatory eicosanoid, lipoxin A4. FASEB Journal. 23(5), 1503–1509 (2009).
Medline CASGoogle Scholar
83. Pamplona FA, Menezes-de-Lima O Jr, Takahashi RN. Aspirin-triggered lipoxin induces CB1-dependent catalepsy in mice. Neurosc.i Lett. 470(1), 33–37 (2010).
Medline CASGoogle Scholar
84. Pamplona FA, Ferreira J, Menezes de Lima O Jr et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl Acad. Sci. USA 109(51), 21134–21139 (2012).
Medline CASGoogle Scholar
85. Gomes I, Grushko JS, Golebiewska U et al. Novel endogenous peptide agonists of cannabinoid receptors. The FASEB Journal. 23(9), 3020–3029 (2009). doi:10.1096/fj.09-132142.
Medline CASGoogle Scholar
86. Hofer SC, Ralvenius WT, Gachet MS, Fritschy JM, Zeilhofer HU, Gertsch J. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla. Neuropharmacology 98, 78–89 (2015).
Medline CASGoogle Scholar
87. Gelman JS, Sironi J, Castro LM, Ferro ES, Fricker LD. Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice. J. Neurochem. 113(4), 871–880 (2011).
Google Scholar
88. Bauer M, Chicca A, Tamborrini M et al. Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors. J. Biol. Chem. 287(44), 36944–36967 (2012).
Medline CASGoogle Scholar
89. Petrucci V, Chicca A, Glasmacher S, Paloczi J, Cao Z, Pacher P, Gertsch J. Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci Rep. 7(1), 9560 (2017).
MedlineGoogle Scholar
90. Pistis M, O’Sullivan SE. The role of nuclear hormone receptors in cannabinoid function. Adv Pharmacol. 80, 291–328 (2017).
Medline CASGoogle Scholar
91. Priestley RS, Nickolls SA, Alexander SPH, Kendall DA. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB J. 29(4), 1446–1455 (2015).
Medline CASGoogle Scholar
92. Navarro HA, Howard JL, Pollard GT, Carroll FI. Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br. J. Pharmacol. 156(7), 1178–1184 (2009).
Medline CASGoogle Scholar
93. Hiranita T, Wilkinson DS, Hong WC et al. 2-isoxazol-3-phenyltropane derivatives of cocaine: molecular and atypical system effects at the dopamine transporter. J. Pharmacol. Exp. Ther. 349(2), 297–309 (2014).
MedlineGoogle Scholar
94. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 150(5), 613–623 (2007).
Medline CASGoogle Scholar
95. Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor. Br. J. Pharmacol. 172(20), 4790–4805 (2015).
Medline CASGoogle Scholar
96. Martínez-Pinilla E, Varani K, Reyes-Resina I et al. Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB2 receptors. Front. Pharmacol. 8), 744 (2017).
MedlineGoogle Scholar
97. Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br. J. Pharmacol. 176(10), 1455–1469 (2018).
MedlineGoogle Scholar
98. Hanus LO, Tchilibon S, Ponde DE, Breuer A, Fride E, Mechoulam R. Enantiomeric cannabidiol derivatives: synthesis and binding to cannabinoid receptors. Org. Biomol. Chem. 3(6), 1116–1123 (2005).
Medline CASGoogle Scholar
99. Sabatucci A, Tortolani D, Dainese E, Maccarrone M. In silico mapping of allosteric ligand binding sites in type-1 cannabinoid receptor. Biotechnol. Appl. Biochem. 65(1), 21–28 (2018). •• Presents in silico docking study of the crystal structure of CB1 receptor on endogenous and natural hydrophobic ligands that act as positive allosteric and negative allosteric modulators.
Medline CASGoogle Scholar

Vol. 11, No. 15

Metrics

Downloaded 426 times

History

Received 10 January 2019

Accepted 3 May 2019

Published online 13 September 2019

Published in print August 2019

Information

Keywords

Financial & competing interests disclosure

The authors acknowledge funding from FISM – Fondazione Italiana Sclerosi Multipla - cod 2017/R/16 and financed or co-financed with the ‘5 per mille’ public funding. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Allosteric modulators targeting cannabinoid cb1 and cb2 receptors: implications for drug discovery

Abstract

References