Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target

References

• Roth BL, Kroeze WK. Integrated approaches for genome-wide interrogation of the druggable non-olfactory G protein-coupled receptor superfamily. J Biol Chem. 2015;290:19471–19477. DOI:10.1074/jbc.R115.654764
   PubMed Web of Science ®Google Scholar
• Fredriksson R, Schioth HB. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol. 2005;67:1414–1425. DOI:10.1124/mol.104.009001
   PubMed Web of Science ®Google Scholar
• Zhang X, Eggert US. Non-traditional roles of G protein-coupled receptors in basic cell biology. Mol Biosyst. 2013;9:586–595. DOI:10.1039/c2mb25429h
   PubMed Web of Science ®Google Scholar
• Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006;5:993–996. DOI:10.1038/nrd2199
   PubMed Web of Science ®Google Scholar
• Lagerström MC, Schiöth HB. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov. 2008;7:339–357. DOI:10.1038/nrd2518
   PubMed Web of Science ®Google Scholar
• Bradley SJ, Tobin AB. Design of next-generation G protein-coupled receptor drugs: linking novel pharmacology and in vivo animal models. Annu Rev Pharmacol Toxicol. 2016;56:535–559. DOI:10.1146/annurev-pharmtox-011613-140012
   PubMed Web of Science ®Google Scholar
• Venkatakrishnan AJ, Deupi X, Lebon G, et al. Molecular signatures of G-protein-coupled receptors. Nature. 2013;494:185–194. DOI:10.1038/nature11896
   PubMed Web of Science ®Google Scholar
• Janero DR, Lindsley L, Vemuri VK, et al. Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk. Expert Opin Drug Discov. 2011;6:995–1025. DOI:10.1517/17460441.2011.608063
   PubMed Web of Science ®Google Scholar
• Jacobson KA. Structure-based approaches to ligands for G-protein-coupled adenosine and P2Y receptors, from small molecules to nanoconjugates. J Med Chem. 2013;56:3749–3767. DOI:10.1021/jm400422s
   PubMed Web of Science ®Google Scholar
• Guarnera E, Berezovsky IN. Allosteric sites: remote control in regulation of protein activity. Curr Opin Struct Biol. 2016;37:1–8. DOI:10.1016/j.sbi.2015.10.004 .
   PubMed Web of Science ®Google Scholar
• Gentry PR, Sexton PM, Christopoulos A. Novel allosteric modulators of G protein-coupled receptors. J Biol Chem. 2015;290:19478–19488. DOI:10.1074/jbc.R115.662759 .
   PubMed Web of Science ®Google Scholar
• Edelstein SJ, Le Novère N. Cooperativity of allosteric receptors. J Mol Biol. 2013;425:1424–1432. DOI:10.1016/j.jmb.2013.03.011
   PubMed Web of Science ®Google Scholar
• Christopoulos A. Advances in G protein-coupled receptor allostery: from function to structure. Mol Pharmacol. 2014;86:463–478. DOI:10.1124/mol.114.094342
   PubMed Web of Science ®Google Scholar
• Hertig S, Latorraca NR, Dror RO. Revealing atomic-level mechanisms of protein allostery with molecular dynamics simulations. PLoS Comput Biol. 2016;12:e1004746. published online 10 June 2016. DOI:10.1371/journal.pcbi.1004746
   PubMed Web of Science ®Google Scholar
• Guidolin D, Agnati LF, Marcoli M, et al. G-protein-coupled receptor type A heteromers as an emerging therapeutic target. Expert Opin Ther Targets. 2015;19:265–283. DOI:10.1517/14728222.2014.981155
   PubMed Web of Science ®Google Scholar
• Cavanaugh A, Huang Y, Breitwieser GE. Behind the curtain: cellular mechanisms for allosteric modulation of calcium-sensing receptors. Br J Pharmacol. 2012;165:1670–1677. DOI:10.1111/j.1476-5381.2011.01403.x
   PubMed Web of Science ®Google Scholar
• Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov. 2009;8:41–54. DOI:10.1038/nrd2760
   PubMed Web of Science ®Google Scholar
• Wenthur CJ, Gentry PR, Mathews TP, et al. Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol. 2014;54:165–184. DOI:10.1146/annurev-pharmtox-010611-134525
   PubMed Web of Science ®Google Scholar
• Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov. 2013;12:630–644. DOI:10.1038/nrd4052
   PubMed Web of Science ®Google Scholar
• Rankovic Z, Brust TF, Bohn LM. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg Med Chem Lett. 2016;26:241–250. DOI:10.1016/j.bmcl.2015.12.024
   PubMed Web of Science ®Google Scholar
• Gao ZG, Jacobson KA. Allosteric modulation and functional selectivity of G protein-coupled receptors. Drug Discov Today Technol. 2013;10:e237–243. DOI:10.1016/j.ddtec.2012.08.004
   PubMedGoogle Scholar
• Kenakin T. Allosteric drugs and seven transmembrane receptors. Curr Top Med Chem. 2013;13:5–13.
   PubMed Web of Science ®Google Scholar
• Nickols HH, Conn PJ. Development of allosteric modulators of GPCRs for treatment of CNS disorders. Neurobiol Dis. 2014;61:55–71. DOI:10.1016/j.nbd.2013.09.013
   PubMed Web of Science ®Google Scholar
• Lindsley CW, Emmitte KA, Hopkins CR, et al. Practical strategies and concepts in GPCR allosteric modulator discovery: recent advances with metabotropic glutamate receptors. Chem Rev. 2016;116:6707–6741. DOI:10.1021/acs.chemrev.5b00656 .
   PubMed Web of Science ®Google Scholar
• Miao Y, Nichols SE, McCammon JA. Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor. Chem Biol Drug Des. 2014;83:237–246. DOI:10.1111/cbdd.12233
   PubMed Web of Science ®Google Scholar
• Horenstein NA, Papke RL, Kulkarni AR, et al. Critical molecular determinants of α7 nicotinic acetylcholine receptor allosteric activation: separation of direct allosteric activation and positive allosteric modulation. J Biol Chem. 2016;291:5049–5067. DOI:10.1074/jbc.M115.692392
   PubMed Web of Science ®Google Scholar
• Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–525. DOI:10.1016/j.biopsych.2015.07.028
   PubMed Web of Science ®Google Scholar
• Hurst DP, Schmeisser M, Reggio PH. Endogenous lipid activated G protein-coupled receptors: emerging structural features from crystallography and molecular dynamics simulations. Chem Phys Lipids. 2013;169:46–56. DOI:10.1016/j.chemphyslip.2013.01.009
   PubMed Web of Science ®Google Scholar
• Stadel R, Ahn KH, Kendall DA. The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. J Neurochem. 2011;117:1–18. DOI:10.1111/j.1471-4159.2011.07186.x
   PubMed Web of Science ®Google Scholar
• Nebane NM, Kellie B, Song ZH. The effects of charge-neutralizing mutation D6.30N on the functions of CB1 and CB2 cannabinoid receptors. FEBS Lett. 2006;580:5392–5398. DOI:10.1016/j.febslet.2006.09.001
   PubMed Web of Science ®Google Scholar
• Ahn KH, Scott CE, Abrol R, et al. Computationally-predicted CB1 cannabinoid receptor mutants show distinct patterns of salt-bridges that correlate with their level of constitutive activity reflected in G protein coupling levels, thermal stability, and ligand binding. Proteins. 2013;81:1304–1317. DOI:10.1002/prot.24264
   PubMed Web of Science ®Google Scholar
• Baillie GL, Horswill JG, Anavi-Goffer S, et al. CB1 receptor allosteric modulators display both agonist and signaling pathway specificity. Mol Pharmacol. 2013;83:322–338. DOI:10.1124/mol.112.080879
   PubMed Web of Science ®Google Scholar
• Shore DM, Baillie GL, 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. 2014;289:5828–5845. DOI:10.1074/jbc.M113.478495
   PubMed Web of Science ®Google Scholar
• 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. 2012;287:33873–33882. DOI:10.1074/jbc.M112.352328
   PubMed Web of Science ®Google Scholar
• 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. 2015;5:15453. published online 20 October 2015. DOI:10.1038/srep15453
   PubMed Web of Science ®Google Scholar
• Laprairie RB, Kulkarni AR, Kulkarni PM, et al. Mapping cannabinoid 1 receptor allosteric site(s): critical molecular determinant and signaling profile of GAT100, a novel, potent, and irreversibly binding probe. ACS Chem Neurosci. 2016;7:776–798. DOI:10.1021/acschemneuro.6b00041 .
   PubMed Web of Science ®Google Scholar
• Zvonok N, Xu W, Williams J, et al. Mass spectrometry-based GPCR proteomics: comprehensive characterization of the human cannabinoid 1 receptor. J Proteome Res. 2010;9:1746–1753. DOI:10.1021/pr900870p
   PubMed Web of Science ®Google Scholar
• Hurst DP, Grossfield A, Lynch DL, et al. A lipid pathway for ligand binding is necessary for a cannabinoid G protein-coupled receptor. J Biol Chem. 2010;285:17954–17964. DOI:10.1074/jbc.M109.041590
   PubMed Web of Science ®Google Scholar
• Pertwee RG. Endocannabinoids and their pharmacological actions. Handb Exp Pharmacol. 2015;231:1–37. DOI:10.1007/978-3-319-20825-1_1 .
   PubMedGoogle Scholar
• Howlett AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17:1382–13893.
   PubMed Web of Science ®Google Scholar
• Ohno-Shosaku T, Kano M. Endocannabinoid-mediated retrograde modulation of synaptic transmission. Curr Opin Neurobiol. 2014;29:1–8. DOI:10.1016/j.conb.2014.03.017
   PubMed Web of Science ®Google Scholar
• Ligresti A, De Petrocellis L, Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev. 2016;96:1593–1659. DOI:10.1152/physrev.00002.2016
   PubMed Web of Science ®Google Scholar
• Benyó Z, Ruisanchez É, Leszl-Ishiguro M, et al. Endocannabinoids in cerebrovascular regulation. Am J Physiol Heart Circ Physiol. 2016;310:H785–H801. DOI:10.1152/ajpheart.00571.2015
   PubMed Web of Science ®Google Scholar
• Cooper ME, Regnell SE. The hepatic cannabinoid 1 receptor as a modulator of hepatic energy state and food intake. Br J Clin Pharmacol. 2014;77:21–30. DOI:10.1111/bcp.12102
   PubMed Web of Science ®Google Scholar
• Battista N, Bari M, Maccarrone M. Endocannabinoids and reproductive events in health and disease. Handb Exp Pharmacol. 2015;231:341–365. DOI:10.1007/978-3-319-20825-1_12
   PubMedGoogle Scholar
• Panagis G, Mackey B, Vlachou S. Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: a step back into the future. Front Psychiatry. 2014;5:92. DOI:10.3389/fpsyt.2014.00092
   PubMed Web of Science ®Google Scholar
• Iannotti FA, Di Marzo V, Petrosino S. Endocannabinoids and endocannabinoid-related mediators: targets, metabolism and role in neurological disorders. Prog Lipid Res. 2016;62:107–128. DOI:10.1016/j.plipres.2016.02.002
   PubMed Web of Science ®Google Scholar
• Maccarrone M, Bab I, Bíró T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36:277–296. DOI:10.1016/j.tips.2015.02.008
   PubMed Web of Science ®Google Scholar
• Vasileiou I, Fotopoulou G, Matzourani M, et al. Evidence for the involvement of cannabinoid receptors’ polymorphisms in the pathophysiology of human diseases. Expert Opin Ther Targets. 2013;17:363–377. DOI:10.1517/14728222.2013.754426
   PubMed Web of Science ®Google Scholar
• Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA. 2015;313:2474–2483. DOI:10.1001/jama.2015.6199
   PubMed Web of Science ®Google Scholar
• Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456–2473. DOI:10.1001/jama.2015.6358
   PubMed Web of Science ®Google Scholar
• Vemuri VK, Makriyannis A. Medicinal chemistry of cannabinoids. Clin Pharmacol Ther. 2015;97:553–558. DOI:10.1002/cpt.115
   PubMed Web of Science ®Google Scholar
• McPartland JM, Duncan M, Di Marzo V, et al. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737–753. DOI:10.1111/bph.12944
   PubMed Web of Science ®Google Scholar
• Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367:3353–3363. DOI:10.1098/rstb.2011.0381
   PubMed Web of Science ®Google Scholar
• GW Pharmaceuticals provides update on orphan program in childhood epilepsy for Epidiolex®. [cited 2016 Oct 1]. Available from: http://www.gwpharm.com/GW%20Pharmaceuticals%20Provides%20Update%20on%20Orphan%20Program%20in%20Childhood%20Epilepsy%20for%20Epidiolex.aspx
   Google Scholar
• Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009;14:43–65. DOI:10.1517/14728210902736568
   PubMed Web of Science ®Google Scholar
• Davis MP. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Investig Drugs. 2008;17:85–95. DOI:10.1517/13543784.17.1.85
   PubMed Web of Science ®Google Scholar
• Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles. Diabetes Obes Metab. 2016;18:558–570. DOI:10.1111/dom.12657
   PubMed Web of Science ®Google Scholar
• Tait RJ, Caldicott D, Mountain D, et al. A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clin Toxicol. 2016;54:1–13. DOI:10.3109/15563650.2015.1110590
   PubMed Web of Science ®Google Scholar
• van Amsterdam J, Brunt T, van den Brink W. The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects. J Psychopharmacol. 2015;29:254–263. DOI:10.1177/0269881114565142
   PubMed Web of Science ®Google Scholar
• Meye FJ, Ramakers GM, Adan RA. The vital role of constitutive GPCR activity in the mesolimbic dopamine system. Transl Psychiatry. 2014;4:e361. Published online 11 February 2014. DOI:10.1038/tp.2013.130
   PubMed Web of Science ®Google Scholar
• Kunos G, Osei-Hyiaman D, Bátkai S, et al. Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain? Trends Pharmacol Sci. 2009;30:1–7. DOI:10.1016/j.tips.2008.10.001
   PubMed Web of Science ®Google Scholar
• Janero DR. Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists. Expert Opin Emerg Drugs. 2012;17:17–29. DOI:10.1517/14728214.2012.660916
   PubMed Web of Science ®Google Scholar
• Price MR, Baillie GL, Thomas A, et al. Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol. 2005;68:1484–1495. DOI:10.1124/mol.105.016162 .
   PubMed Web of Science ®Google Scholar
• Ross RA. Allosterism and cannabinoid CB(1) receptors: the shape of things to come. Trends Pharmacol Sci. 2007;28:567–572. DOI:10.1016/j.tips.2007.10.006
   PubMed Web of Science ®Google Scholar
• 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. 2007;152:805–814. DOI:10.1038/sj.bjp.0707347
   PubMed Web of Science ®Google Scholar
• 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. 2012;287:12070–12082. DOI:10.1074/jbc.M111.316463
   PubMed Web of Science ®Google Scholar
• Wang X, Horswill JG, Whalley BJ, et al. 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. 2011;79:758–767. DOI:10.1124/mol.110.068197
   PubMed Web of Science ®Google Scholar
• 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. 2014;57:3040–3052. DOI:10.1021/jm5000112
   PubMed Web of Science ®Google Scholar
• 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. 2014;57:7758–7769. DOI:10.1021/jm501042u
   PubMed Web of Science ®Google Scholar
• 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. 2015;23:2195–2203. DOI:10.1016/j.bmc.2015.02.058
   PubMed Web of Science ®Google Scholar
• Picone RP, Kendall DA. From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation. Mol Endocrinol. 2015;29:801–813. DOI:10.1210/me.2015-1062
   PubMed Web of Science ®Google Scholar
• Navarro HA, Howard JL, Pollard GT, et al. Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br J Pharmacol. 2009;156:1178–1184. DOI:10.1111/j.1476-5381.2009.00124.x
   PubMed Web of Science ®Google Scholar
• Priestley RS, Nickolls SA, Alexander SP, et al. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB J. 2015;29:1446–1455. DOI:10.1096/fj.14-263053
   PubMed Web of Science ®Google Scholar
• 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. 2012;109:21134–21139. DOI:10.1073/pnas.1202906109
   PubMed Web of Science ®Google Scholar
• Vallée M, Vitiello S, Bellocchio L, et al. Pregnenolone can protect the brain from cannabis intoxication. Science. 2014;343:94–98. DOI:10.1126/science.1243985
   PubMed Web of Science ®Google Scholar
• Laprairie RB, Bagher AM, Kelly ME, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172:4790–4805. DOI:10.1111/bph.13250
   PubMed Web of Science ®Google Scholar
• Khajehali E, Malone DT, Glass M, et al. Biased agonism and biased allosteric modulation at the CB1 cannabinoid receptor. Mol Pharmacol. 2015;88:368–379. DOI:10.1124/mol.115.099192
   PubMed Web of Science ®Google Scholar
• 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. 2012;287:36944–36967. DOI:10.1074/jbc.M112.382481
   PubMed Web of Science ®Google Scholar
• Hofer SC, Ralvenius WT, Gachet MS, et al. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla. Neuropharmacology. 2015;98:78–89. DOI:10.1016/j.neuropharm.2015.03.021
   PubMed Web of Science ®Google Scholar
• Iliff HA, Lynch DL, Kotsikorou E, et al. Parameterization of Org27569: an allosteric modulator of the cannabinoid CB1 G protein-coupled receptor. J Comput Chem. 2011;32:2119–2126. DOI:10.1002/jcc.21794
   PubMed Web of Science ®Google Scholar
• Straiker A, Mitjavila J, Yin D, et al. Aiming for allosterism: evaluation of allosteric modulators of CB1 in a neuronal model. Pharmacol Res. 2015;99:370–376. DOI:10.1016/j.phrs.2015.07.017
   PubMed Web of Science ®Google Scholar
• Ding Y, Qiu Y, Jing L, et al. Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. Pharmacol Res Perspect. 2014;2:e00069. published online 24 August 2014. DOI:10.1002/prp2.69
   PubMedGoogle Scholar
• Gamage TF, Ignatowska-Jankowska BM, Wiley JL, et al. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol. 2014;25:182–185. DOI:10.1097/FBP.0000000000000027
   PubMed Web of Science ®Google Scholar
• Jing L, Qiu Y, Zhang Y, et al. Effects of the cannabinoid CB₁ receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats. Drug Alcohol Depend. 2014;143:251–256. DOI:10.1016/j.drugalcdep.2014.08.004
   PubMed Web of Science ®Google Scholar
• 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. 2015;40:2948–2959. DOI:10.1038/npp.2015.148
   PubMed Web of Science ®Google Scholar
• Jazayeri A, Dias JM, Marshall FH. From G protein-coupled receptor structure resolution to rational drug design. J Biol Chem. 2015;290:19489–19495. DOI:10.1074/jbc.R115.668251 .
   PubMed Web of Science ®Google Scholar
• Topiol S. X-ray structural information of GPCRs in drug design: what are the limitations and where do we go? Expert Opin Drug Discov. 2013;8:607–620. DOI:10.1517/17460441.2013.783815
   PubMed Web of Science ®Google Scholar
• Merk A, Bartesaghi A, Banerjee S, et al. Breaking Cryo-EM resolution barriers to facilitate drug discovery. Cell. 2016;165:1698–1707. DOI:10.1016/j.cell.2016.05.040
   PubMed Web of Science ®Google Scholar
• Kenakin T. Analytical pharmacology and allosterism: the importance of quantifying drug parameters in drug discovery. Drug Discov Today Technol. 2013;10:e229–235. DOI:10.1016/j.ddtec.2012.07.006
   Google Scholar
• Bennett KA, Doré AS, Christopher JA, et al. Structures of mGluRs shed light on the challenges of drug development of allosteric modulators. Curr Opin Pharmacol. 2015;20:1–7. DOI:10.1016/j.coph.2014.09.022
   PubMed Web of Science ®Google Scholar
• Zhu S, Paoletti P. Allosteric modulators of NMDA receptors: multiple sites and mechanisms. Curr Opin Pharmacol. 2015;20:14–23. DOI:10.1016/j.coph.2014.10.009
   PubMed Web of Science ®Google Scholar
• Munk C, Harpsøe K, Hauser AS, et al. Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr Opin Pharmacol. 2016;30:51–58. DOI:10.1016/j.coph.2016.07.003
   PubMed Web of Science ®Google Scholar
• Ehlert FJ. Functional studies cast light on receptor states. Trends Pharmacol Sci. 2015;36:596–604. DOI:10.1016/j.tips.2015.05.008
   PubMed Web of Science ®Google Scholar
• Changeux JP, Christopoulos A. Allosteric modulation as a unifying mechanism for receptor function and regulation. Cell. 2016;166:1084–1102. DOI:10.1016/j.cell.2016.08.015
   PubMed Web of Science ®Google Scholar
• Martí-Solano M, Schmidt D, Kolb P, et al. Drugging specific conformational states of GPCRs: challenges and opportunities for computational chemistry. Drug Discov Today. 2016;21:625–631. DOI:10.1016/j.drudis.2016.01.009
   PubMed Web of Science ®Google Scholar
• Shonberg J, Kling RC, Gmeiner P, et al. GPCR crystal structures: medicinal chemistry in the pocket. Bioorg Med Chem. 2015;23:3880–3906. DOI:10.1016/j.bmc.2014.12.034
   PubMed Web of Science ®Google Scholar
• Fenalti G, Giguere PM, Katritch V, et al. Molecular control of delta-opioid receptor signalling. Nature. 2014;506:191–196. DOI:10.1038/nature12944
   PubMed Web of Science ®Google Scholar
• Huang W, Manglik A, Venkatakrishnan AJ, et al. Structural insights into µ-opioid receptor activation. Nature. 2015;524:315–321. DOI:10.1038/nature14886
   PubMed Web of Science ®Google Scholar
• Kruse AC, Ring AM, Manglik A, et al. Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature. 2013;504:101–106. DOI:10.1038/nature12735
   PubMed Web of Science ®Google Scholar
• Thal DM, Sun B, Feng D, et al. Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature. 2016;531:335–340. DOI:10.1038/nature17188
   PubMed Web of Science ®Google Scholar
• Wootten D, Reynolds CA, Koole C, et al. A hydrogen-bonded polar network in the core of the glucagon-like peptide-1 receptor is a fulcrum for biased agonism: lessons from class B crystal structures. Mol Pharmacol. 2016;89(3):335–347. DOI:10.1124/mol.115.101246
   PubMed Web of Science ®Google Scholar
• Wu H, Wang C, Gregory KJ, et al. Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science. 2014;344:58–64. DOI:10.1126/science.1249489
   PubMed Web of Science ®Google Scholar
• Doré AS, Okrasa K, Patel JC, et al. Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature. 2014;511:557–562. DOI:10.1038/nature13396
   PubMed Web of Science ®Google Scholar
• Bartuzi D, Kaczor AA, Matosiuk D. Activation and allosteric modulation of human μ opioid receptor in molecular dynamics. J Chem Inf Model. 2015;55:2421–2434. DOI:10.1021/acs.jcim.5b00280
   PubMed Web of Science ®Google Scholar
• Feng Z, Hu G, Ma S, et al. Computational advances for the sevelopment of allosteric modulators and bitopic ligands in G protein-coupled receptors. Aaps J. 2015;17:1080–1095. DOI:10.1208/s12248-015-9776-y
   PubMed Web of Science ®Google Scholar
• Shang Y, Yeatman HR, Provasi D, et al. Proposed mode of binding and action of positive allosteric modulators at opioid receptors. ACS Chem Biol. 2016;11:1220–1229. DOI:10.1021/acschembio.5b00712
   PubMed Web of Science ®Google Scholar
• Deganutti G, Cuzzolin A, Ciancetta A, et al. Understanding allosteric interactions in G protein-coupled receptors using supervised molecular dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000. Bioorg Med Chem. 2015;23:4065–4071. DOI:10.1016/j.bmc.2015.03.039
   PubMed Web of Science ®Google Scholar
• Isogai S, Deupi X, Opitz C, et al. Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor. Nature. 2016;530:237–241. DOI:10.1038/nature16577
   PubMed Web of Science ®Google Scholar
• Sounier R, Mas C, Steyaert J, et al. Propagation of conformational changes during μ-opioid receptor activation. Nature. 2015;524:375–378. DOI:10.1038/nature14680
   PubMed Web of Science ®Google Scholar
• Chan WY, McKinzie DL, Bose S, et al. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci USA. 2008;105:10978–10983. DOI:10.1073/pnas.0800567105
   PubMed Web of Science ®Google Scholar
• Valant C, Felder CC, Sexton PM, et al. Probe dependence in the allosteric modulation of a G protein-coupled receptor: implications for detection and validation of allosteric ligand effects. Mol Pharmacol. 2012;81:41–52. DOI:10.1124/mol.111.074872
   PubMed Web of Science ®Google Scholar
• Khatri A, Burger PB, Swanger SA, et al. Structural determinants and mechanism of action of a GluN2C-selective NMDA receptor positive allosteric modulator. Mol Pharmacol. 2014;86:548–560. DOI:10.1124/mol.114.094516
   PubMed Web of Science ®Google Scholar
• Farinha A, Lavreysen H, Peeters L, et al. Molecular determinants of positive allosteric modulation of the human metabotropic glutamate receptor 2. Br J Pharmacol. 2015;172:2383–2396. DOI:10.1111/bph.13065
   PubMed Web of Science ®Google Scholar
• Dror RO, Green HF, Valant C, et al. Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature. 2013;503:295–299. DOI:10.1038/nature12595
   PubMed Web of Science ®Google Scholar
• Rovira X, Malhaire F, Scholler P, et al. Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J. 2015;29:116–130. DOI:10.1096/fj.14-257287
   PubMed Web of Science ®Google Scholar
• Jang JW, Cho NC, Min SJ, et al. Novel scaffold identification of mGlu1 receptor negative allosteric modulators using a hierarchical virtual screening approach. Chem Biol Drug Des. 2016;87:239–256. DOI:10.1111/cbdd.12654
   PubMed Web of Science ®Google Scholar
• Zhang D, Zhao Q, Wu B. Structural studies of G protein-coupled receptors. Mol Cells. 2015;38:836–842. DOI:10.14348/molcells.2015.0263
   PubMed Web of Science ®Google Scholar
• McAllister SD, Rizvi G, Anavi-Goffer S, et al. An aromatic microdomain at the cannabinoid CB(1) receptor constitutes an agonist/inverse agonist binding region. J Med Chem. 2003;46:5139–5152. DOI:10.1021/jm0302647
   PubMed Web of Science ®Google Scholar
• Gregory KJ, Velagaleti R, Thal DM, et al. Clickable photoaffinity ligands for metabotropic glutamate receptor 5 based on select acetylenic negative allosteric modulators. ACS Chem Biol. 2016;11:1870–1879. DOI:10.1021/acschembio.6b00026
   PubMed Web of Science ®Google Scholar
• Bueno AB, Showalter AD, Wainscott DB, et al. Positive allosteric modulation of the glucagon-like peptide-1 receptor by diverse electrophiles. J Biol Chem. 2016;291:10700–10715. DOI:10.1074/jbc.M115.696039
   PubMed Web of Science ®Google Scholar
• Huber T, Sakmar TP. Chemical biology methods for investigating G protein-coupled receptor signaling. Chem Biol. 2014;21:1224–1237. DOI:10.1016/j.chembiol.2014.08.009
   PubMedGoogle Scholar
• Weichert D, Gmeiner P. Covalent molecular probes for class A G protein-coupled receptors: advances and applications. ACS Chem Biol. 2015;10:1376–1386. DOI:10.1021/acschembio.5b00070
   PubMed Web of Science ®Google Scholar
• Janero DR, Yaddanapudi S, Zvonok N, et al. Molecular-interaction and signaling profiles of AM3677, a novel covalent agonist selective for the cannabinoid 1 receptor. ACS Chem Neurosci. 2015;6:1400–1410. DOI:10.1021/acschemneuro.5b00090
   PubMed Web of Science ®Google Scholar
• Szymanski DW, Papanastasiou M, Melchior K, et al. Mass spectrometry-based proteomics of human cannabinoid receptor 2: covalent cysteine 6.47(257)-ligand interaction affording megagonist receptor activation. J Proteome Res. 2011;10:4789–4798. DOI:10.1021/pr2005583
   PubMed Web of Science ®Google Scholar
• Pei Y, Mercier RW, Anday JK, et al. Ligand-binding architecture of human CB2 cannabinoid receptor: evidence for receptor subtype-specific binding motif and modeling GPCR activation. Chem Biol. 2008;15:1207–1219. DOI:10.1016/j.chembiol.2008.10.011
   PubMed Web of Science ®Google Scholar
• Fay JF, Farrens DL. Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1. Proc Natl Acad Sci USA. 2015;112:8469–8474. DOI:10.1073/pnas.1500895112
   PubMed Web of Science ®Google Scholar
• 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. 2016;59:44–60. DOI:10.1021/acs.jmedchem.5b01303
   PubMed Web of Science ®Google Scholar
• Doorn JA, Petersen DR. Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2- nonenal and 4-oxo-2-nonenal. Chem Res Toxicol. 2002;15:1445−1450. DOI:10.1021/tx025590o
   PubMed Web of Science ®Google Scholar
• Tahtaoui C, Balestre MN, Klotz P, et al. Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors. J Biol Chem. 2003;278:40010–40019. DOI:10.1074/jbc.M301128200
   PubMed Web of Science ®Google Scholar
• Wu X, Zhou QH, Xu K. Are isothiocyanates potential anti-cancer drugs? Acta Pharmacol Sin. 2009;30:501−512. DOI:10.1038/aps.2009.50
   PubMed Web of Science ®Google Scholar
• Qiao CJ, Ali HI, Ahn KH, et al. Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor. Eur J Med Chem. 2016;121:517–529. DOI:10.1016/j.ejmech.2016.05.044
   PubMed Web of Science ®Google Scholar
• Andersson H, D’Antona AM, Kendall DA, et al. Membrane assembly of the cannabinoid receptor 1: impact of a long N-terminal tail. Mol Pharmacol. 2003;64:570–577. DOI:10.1124/mol.64.3.570
   PubMed Web of Science ®Google Scholar
• Fay JF, Farrens DL. The membrane proximal region of the cannabinoid receptor CB1 N-terminus can allosterically modulate ligand affinity. Biochemistry. 2013;52:8286–8294. DOI:10.1021/bi400842k
   PubMed Web of Science ®Google Scholar
• Garland SL. Are GPCRs still a source of new targets? J Biomol Screen. 2013;18:947–966. DOI:10.1177/1087057113498418
   PubMed Web of Science ®Google Scholar
• Kinch MS. 2015 in review: FDA approval of new drugs. Drug Discov Today. 2016;21:1046–1050. DOI:10.1016/j.drudis.2016.04.008
   PubMed Web of Science ®Google Scholar
• Jacobson KA. New paradigms in GPCR drug discovery. Biochem Pharmacol. 2015;98:541–555. DOI:10.1016/j.bcp.2015.08.085
   PubMed Web of Science ®Google Scholar
• Miao Y, McCammon JA. G-protein coupled receptors: advances in simulation and drug discovery. Curr Opin Struct Biol. 2016;41:83–89. DOI:10.1016/j.sbi.2016.06.008
   PubMed Web of Science ®Google Scholar
• Desai AJ, Henke BR, Miller LJ. Elimination of a cholecystokinin receptor agonist ‘trigger’ in an effort to develop positive allosteric modulators without intrinsic agonist activity. Bioorg Med Chem Lett. 2015;25:1849–1855. DOI:10.1016/j.bmcl.2015.03.051
   PubMed Web of Science ®Google Scholar
• Noetzel MJ, Rook JM, Vinson PN, et al. Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function. Mol Pharmacol. 2012;81:120–133. DOI:10.1124/mol.111.075184
   PubMed Web of Science ®Google Scholar
• Parmentier-Batteur S, Hutson PH, Menzel K, et al. Mechanism based neurotoxicity of mGlu5 positive allosteric modulators–development challenges for a promising novel antipsychotic target. Neuropharmacology. 2014;82:161–173. DOI:10.1016/j.neuropharm.2012.12.003
   PubMed Web of Science ®Google Scholar
• Bridges TM, Rook JM, Noetzel MJ, et al. Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. Drug Metab Dispos. 2013;41:1703–1714. DOI:10.1124/dmd.113.052084
   PubMed Web of Science ®Google Scholar
• Bagdas D, Wilkerson JL, Kulkarni A, et al. The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain. Br J Pharmacol. 2016;173:2506–2520. DOI:10.1111/bph.13528
   PubMed Web of Science ®Google Scholar
• Mah R, Thomas JR, Shafer CM. Drug discovery considerations in the development of covalent drugs. Bioorg Med Chem Lett. 2014;24:33–39. DOI:10.1016/j.bmcl.2013.10.003
   PubMed Web of Science ®Google Scholar
• Nussinov R, Tsai CJ. The design of covalent allosteric drugs. Annu Rev Pharmacol Toxicol. 2015;55:249–267. DOI:10.1146/annurev-pharmtox-010814-124401
   PubMed Web of Science ®Google Scholar
• Schreiber SL, Kotz JD, Li M, et al. Advancing biological understanding and therapeutics discovery with small-molecule probes. Cell. 2015;161:1252–1265. DOI:10.1016/j.cell.2015.05.023
   PubMed Web of Science ®Google Scholar
• Langmead CJ. Determining allosteric modulator mechanism of action: integration of radioligand binding and functional assay data. Methods Mol Biol. 2011;746:195–209. DOI:10.1007/978-1-61779-126-0_10
   PubMedGoogle Scholar
• Rocheville M, Martin J, Jerman J, et al. Mining the potential of label-free biosensors for seven-transmembrane receptor drug discovery. Prog Mol Biol Transl Sci. 2013;115:123–142. DOI:10.1016/B978-0-12-394587-7.00003-8
   PubMed Web of Science ®Google Scholar
• Janero DR. The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential. Expert Opin Drug Discov. 2014;9:847–858.
   PubMed Web of Science ®Google Scholar
• Aristotelous T, Hopkins AL, Navratilova I. Surface plasmon resonance analysis of seven-transmembrane receptors. Methods Enzymol. 2015;556:499–525. DOI:10.1016/bs.mie.2015.01.016
   PubMed Web of Science ®Google Scholar
• García C, Palomo-Garo C, Gómez-Gálvez Y, et al. Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. Br J Pharmacol. 2016;173:2069–2079. DOI:10.1111/bph.13215
   PubMed Web of Science ®Google Scholar
• Cawston EE, Connor M, Di Marzo V, et al. Distinct temporal fingerprint for cyclic adenosine monophosphate (cAMP) signaling of indole-2-carboxamides as allosteric modulators of the cannabinoid receptors. J Med Chem. 2015;58:5979–5988. DOI:10.1021/acs.jmedchem.5b00579
   PubMed Web of Science ®Google Scholar