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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Overcoming the Psychiatric Side Effects of the Cannabinoid CB1 Receptor Antagonists: Current Approaches for Therapeutics Development

Author(s): Thuy Nguyen, Brian F. Thomas and Yanan Zhang*

Volume 19, Issue 16, 2019

Page: [1418 - 1435] Pages: 18

DOI: 10.2174/1568026619666190708164841

Price: $65

Abstract

The Cannabinoid CB1 Receptor (CB1R) is involved in a variety of physiological pathways and has long been considered a golden target for therapeutic manipulation. A large body of evidence in both animal and human studies suggests that CB1R antagonism is highly effective for the treatment of obesity, metabolic disorders and drug addiction. However, the first-in-class CB1R antagonist/inverse agonist, rimonabant, though demonstrating effectiveness for obesity treatment and smoking cessation, displays serious psychiatric side effects, including anxiety, depression and even suicidal ideation, resulting in its eventual withdrawal from the European market. Several strategies are currently being pursued to circumvent the mechanisms leading to these side effects by developing neutral antagonists, peripherally restricted ligands, and allosteric modulators. In this review, we describe the progress in the development of therapeutics targeting the CB1R in the last two decades.

Keywords: CB1 receptor, Psychiatric side effects, Neutral antagonists, Peripherally restricted antagonists, Allosteric modulators, Therapeutics development.

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[1]
Pertwee, R.G. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2012, 367(1607), 3353-3363.
[http://dx.doi.org/10.1098/rstb.2011.0381] [PMID: 23108552]
[2]
Klein, T.W. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat. Rev. Immunol., 2005, 5(5), 400-411.
[http://dx.doi.org/10.1038/nri1602] [PMID: 15864274]
[3]
De Petrocellis, L.; Cascio, M.G.; Di Marzo, V. The endocannabinoid system: A general view and latest additions. Br. J. Pharmacol., 2004, 141(5), 765-774.
[http://dx.doi.org/10.1038/sj.bjp.0705666] [PMID: 14744801]
[4]
Porter, A.C.; Felder, C.C. The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol. Ther., 2001, 90(1), 45-60.
[http://dx.doi.org/10.1016/S0163-7258(01)00130-9] [PMID: 11448725]
[5]
Harkany, T.; Guzmán, M.; Galve-Roperh, I.; Berghuis, P.; Devi, L.A.; Mackie, K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol. Sci., 2007, 28(2), 83-92.
[http://dx.doi.org/10.1016/j.tips.2006.12.004] [PMID: 17222464]
[6]
Kreitzer, A.C.; Regehr, W.G. Retrograde signaling by endocannabinoids. Curr. Opin. Neurobiol., 2002, 12(3), 324-330.
[http://dx.doi.org/10.1016/S0959-4388(02)00328-8] [PMID: 12049940]
[7]
Di Marzo, V. Targeting the endocannabinoid system: To enhance or reduce? Nat. Rev. Drug Discov., 2008, 7(5), 438-455.
[http://dx.doi.org/10.1038/nrd2553] [PMID: 18446159]
[8]
Muccioli, G.G.; Lambert, D.M. Current knowledge on the antagonists and inverse agonists of cannabinoid receptors. Curr. Med. Chem., 2005, 12(12), 1361-1394.
[http://dx.doi.org/10.2174/0929867054020891] [PMID: 15974990]
[9]
Jagerovic, N.; Fernandez-Fernandez, C.; Goya, P. CB1 cannabinoid antagonists: Structure-activity relationships and potential therapeutic applications. Curr. Top. Med. Chem., 2008, 8(3), 205-230.
[http://dx.doi.org/10.2174/156802608783498050] [PMID: 18289089]
[10]
Azar, S.; Sherf-Dagan, S.; Nemirovski, A.; Webb, M.; Raziel, A.; Keidar, A.; Goitein, D.; Sakran, N.; Shibolet, O.; Tam, J.; Zelber-Sagi, S. Circulating endocannabinoids are reduced following bariatric surgery and associated with improved metabolic homeostasis in humans. Obes. Surg., 2019, 29(1), 268-276.
[PMID: 30244333]
[11]
Monteleone, A.M.; Di Marzo, V.; Monteleone, P.; Dalle Grave, R.; Aveta, T.; Ghoch, M.E.; Piscitelli, F.; Volpe, U.; Calugi, S.; Maj, M. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity. Eur. J. Nutr., 2016, 55(4), 1799-1805.
[http://dx.doi.org/10.1007/s00394-016-1153-9] [PMID: 26759262]
[12]
van Eyk, H.J.; van Schinkel, L.D.; Kantae, V.; Dronkers, C.E.A.; Westenberg, J.J.M.; de Roos, A.; Lamb, H.J.; Jukema, J.W.; Harms, A.C.; Hankemeier, T.; van der Stelt, M.; Jazet, I.M.; Rensen, P.C.N.; Smit, J.W.A. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes. Nutr. Diabetes, 2018, 8(1), 6.
[http://dx.doi.org/10.1038/s41387-017-0016-7] [PMID: 29343706]
[13]
Perkins, J.M.; Davis, S.N. Endocannabinoid system overactivity and the metabolic syndrome: prospects for treatment. Curr. Diab. Rep., 2008, 8(1), 12-19.
[http://dx.doi.org/10.1007/s11892-008-0004-3] [PMID: 18366993]
[14]
Duffy, D.; Rader, D. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity. Trends Cardiovasc. Med., 2007, 17(2), 35-43.
[http://dx.doi.org/10.1016/j.tcm.2006.11.003] [PMID: 17292044]
[15]
Després, J.P.; Golay, A.; Sjöström, L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med., 2005, 353(20), 2121-2134.
[http://dx.doi.org/10.1056/NEJMoa044537] [PMID: 16291982]
[16]
Van Gaal, L.F.; Rissanen, A.M.; Scheen, A.J.; Ziegler, O.; Rössner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet, 2005, 365(9468), 1389-1397.
[http://dx.doi.org/10.1016/S0140-6736(05)66374-X] [PMID: 15836887]
[17]
Pi-Sunyer, F.X.; Aronne, L.J.; Heshmati, H.M.; Devin, J.; Rosenstock, J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA, 2006, 295(7), 761-775.
[http://dx.doi.org/10.1001/jama.295.7.761] [PMID: 16478899]
[18]
Scheen, A.J.; Finer, N.; Hollander, P.; Jensen, M.D.; Van Gaal, L.F. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet, 2006, 368(9548), 1660-1672.
[http://dx.doi.org/10.1016/S0140-6736(06)69571-8] [PMID: 17098084]
[19]
Rosenstock, J.; Hollander, P.; Chevalier, S.; Iranmanesh, A.; Group, S.S. SERENADE: the study evaluating rimonabant efficacy in drug-naive diabetic patients: effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes. Diabetes Care, 2008, 31(11), 2169-2176.
[http://dx.doi.org/10.2337/dc08-0386] [PMID: 18678611]
[20]
Després, J.P.; Ross, R.; Boka, G.; Alméras, N.; Lemieux, I. Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-Lipids trial. Arterioscler. Thromb. Vasc. Biol., 2009, 29(3), 416-423.
[http://dx.doi.org/10.1161/ATVBAHA.108.176362] [PMID: 19112166]
[21]
Steinberg, M.B.; Foulds, J. Rimonabant for treating tobacco dependence. Vasc. Health Risk Manag., 2007, 3(3), 307-311.
[PMID: 17703638]
[22]
Huestis, M.A.; Boyd, S.J.; Heishman, S.J.; Preston, K.L.; Bonnet, D.; Le Fur, G.; Gorelick, D.A. Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology (Berl.), 2007, 194(4), 505-515.
[http://dx.doi.org/10.1007/s00213-007-0861-5] [PMID: 17619859]
[23]
Kirkham, T.C. Taranabant cuts the fat: new hope for cannabinoid-based obesity therapies? Cell Metab., 2008, 7(1), 1-2.
[http://dx.doi.org/10.1016/j.cmet.2007.12.006] [PMID: 18177717]
[24]
Bergman, J.; Delatte, M.S.; Paronis, C.A.; Vemuri, K.; Thakur, G.A.; Makriyannis, A. Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties. Physiol. Behav., 2008, 93(4-5), 666-670.
[http://dx.doi.org/10.1016/j.physbeh.2007.11.007] [PMID: 18076956]
[25]
Greasley, P.J.; Clapham, J.C. Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing? Eur. J. Pharmacol., 2006, 553(1-3), 1-9.
[http://dx.doi.org/10.1016/j.ejphar.2006.09.032] [PMID: 17081515]
[26]
Beltramo, M.; Brusa, R.; Mancini, I.; Scandroglio, P. Detecting constitutive activity and protean agonism at cannabinoid-2 receptor. Methods Enzymol., 2010, 484, 31-51.
[http://dx.doi.org/10.1016/B978-0-12-381298-8.00002-2] [PMID: 21036225]
[27]
Osei-Hyiaman, D.; Liu, J.; Zhou, L.; Godlewski, G.; Harvey-White, J.; Jeong, W.I.; Bátkai, S.; Marsicano, G.; Lutz, B.; Buettner, C.; Kunos, G. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J. Clin. Invest., 2008, 118(9), 3160-3169.
[http://dx.doi.org/10.1172/JCI34827] [PMID: 18677409]
[28]
Bensaid, M.; Gary-Bobo, M.; Esclangon, A.; Maffrand, J.P.; Le Fur, G.; Oury-Donat, F.; Soubrié, P. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol. Pharmacol., 2003, 63(4), 908-914.
[http://dx.doi.org/10.1124/mol.63.4.908] [PMID: 12644592]
[29]
Ahn, K.H.; Mahmoud, M.M.; Kendall, D.A. 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(15), 12070-12082.
[http://dx.doi.org/10.1074/jbc.M111.316463] [PMID: 22343625]
[30]
Horswill, J.G.; Bali, U.; Shaaban, S.; Keily, J.F.; Jeevaratnam, P.; Babbs, A.J.; Reynet, C.; Wong Kai In, P. PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br. J. Pharmacol., 2007, 152(5), 805-814.
[http://dx.doi.org/10.1038/sj.bjp.0707347] [PMID: 17592509]
[31]
Fong, T.M. Constitutive activity in cannabinoid receptors. Adv. Pharmacol., 2014, 70, 121-133.
[http://dx.doi.org/10.1016/B978-0-12-417197-8.00004-3] [PMID: 24931194]
[32]
Pertwee, R.G. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci., 2005, 76(12), 1307-1324.
[http://dx.doi.org/10.1016/j.lfs.2004.10.025] [PMID: 15670612]
[33]
Kenakin, T. The physiological significance of constitutive receptor activity. Trends Pharmacol. Sci., 2005, 26, 603-605.
[http://dx.doi.org/10.1016/j.tips.2005.10.007]
[34]
Hurst, D.P.; Lynch, D.L.; Barnett-Norris, J.; Hyatt, S.M.; Seltzman, H.H.; Zhong, M.; Song, Z.H.; Nie, J.; Lewis, D.; Reggio, P.H.N. N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1 receptor. Mol. Pharmacol., 2002, 62(6), 1274-1287.
[http://dx.doi.org/10.1124/mol.62.6.1274] [PMID: 12435794]
[35]
Pan, X.; Ikeda, S.R.; Lewis, D.L. Sr SR 141716A acts as an inverse agonist to increase neuronal voltage-dependent Ca2+ currents by reversal of tonic CB1 cannabinoid receptor activity. Mol. Pharmacol., 1998, 54(6), 1064-1072.
[http://dx.doi.org/10.1124/mol.54.6.1064] [PMID: 9855635]
[36]
Fride, E.; Braun, H.; Matan, H.; Steinberg, S.; Reggio, P.H.; Seltzman, H.H. Inhibition of milk ingestion and growth after administration of a neutral cannabinoid CB1 receptor antagonist on the first postnatal day in the mouse. Pediatr. Res., 2007, 62(5), 533-536.
[http://dx.doi.org/10.1203/PDR.0b013e3181559d42] [PMID: 17805201]
[37]
Hurst, D.; Umejiego, U.; Lynch, D.; Seltzman, H.; Hyatt, S.; Roche, M.; McAllister, S.; Fleischer, D.; Kapur, A.; Abood, M.; Shi, S.; Jones, J.; Lewis, D.; Reggio, P. Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. J. Med. Chem., 2006, 49(20), 5969-5987.
[http://dx.doi.org/10.1021/jm060446b] [PMID: 17004712]
[38]
Seltzman, H.H.; Maitra, R.; Bortoff, K.; Henson, J.; Reggio, P.H.; Wesley, D.; Tam, J. Metabolic profiling of cb1 neutral antagonists. Methods Enzymol., 2017, 593, 199-215.
[http://dx.doi.org/10.1016/bs.mie.2017.06.025] [PMID: 28750803]
[39]
Sink, K.S.; McLaughlin, P.J.; Wood, J.A.; Brown, C.; Fan, P.; Vemuri, V.K.; Peng, Y.; Olszewska, T.; Thakur, G.A.; Makriyannis, A.; Parker, L.A.; Salamone, J.D. The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology, 2008, 33(4), 946-955.
[http://dx.doi.org/10.1038/sj.npp.1301476] [PMID: 17581535]
[40]
Chambers, A.P.; Vemuri, V.K.; Peng, Y.; Wood, J.T.; Olszewska, T.; Pittman, Q.J.; Makriyannis, A.; Sharkey, K.A. A neutral CB1 receptor antagonist reduces weight gain in rat. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2007, 293(6), R2185-R2193.
[http://dx.doi.org/10.1152/ajpregu.00663.2007] [PMID: 17959701]
[41]
Cluny, N.L.; Chambers, A.P.; Vemuri, V.K.; Wood, J.T.; Eller, L.K.; Freni, C.; Reimer, R.A.; Makriyannis, A.; Sharkey, K.A. The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol. Biochem. Behav., 2011, 97(3), 537-543.
[http://dx.doi.org/10.1016/j.pbb.2010.10.013] [PMID: 21056053]
[42]
Järbe, T.U.; LeMay, B.J.; Olszewska, T.; Vemuri, V.K.; Wood, J.T.; Makriyannis, A. Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats. Pharmacol. Biochem. Behav., 2008, 91(1), 84-90.
[http://dx.doi.org/10.1016/j.pbb.2008.06.014] [PMID: 18640150]
[43]
Wills, K.L.; Vemuri, K.; Kalmar, A.; Lee, A.; Limebeer, C.L.; Makriyannis, A.; Parker, L.A. CB1 antagonism: interference with affective properties of acute naloxone-precipitated morphine withdrawal in rats. Psychopharmacology (Berl.), 2014, 231(22), 4291-4300.
[http://dx.doi.org/10.1007/s00213-014-3575-5] [PMID: 24770676]
[44]
Balla, A.; Dong, B.; Shilpa, B.M.; Vemuri, K.; Makriyannis, A.; Pandey, S.C.; Sershen, H.; Suckow, R.F.; Vinod, K.Y. Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling. Neuropharmacology, 2018, 131, 200-208.
[http://dx.doi.org/10.1016/j.neuropharm.2017.10.040] [PMID: 29109060]
[45]
Järbe, T.U.; LeMay, B.J.; Vemuri, V.K.; Vadivel, S.K.; Zvonok, A.; Makriyannis, A. Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology (Berl.), 2011, 216(3), 355-365.
[http://dx.doi.org/10.1007/s00213-011-2226-3] [PMID: 21369753]
[46]
Kangas, B.D.; Delatte, M.S.; Vemuri, V.K.; Thakur, G.A.; Nikas, S.P.; Subramanian, K.V.; Shukla, V.G.; Makriyannis, A.; Bergman, J. Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. J. Pharmacol. Exp. Ther., 2013, 344(3), 561-567.
[http://dx.doi.org/10.1124/jpet.112.201962] [PMID: 23287700]
[47]
Schindler, C.W.; Redhi, G.H.; Vemuri, K.; Makriyannis, A.; Le Foll, B.; Bergman, J.; Goldberg, S.R.; Justinova, Z. Blockade of nicotine and cannabinoid reinforcement and relapse by a cannabinoid cb1-receptor neutral antagonist am4113 and inverse agonist rimonabant in squirrel monkeys. Neuropsychopharmacology, 2016, 41(9), 2283-2293.
[http://dx.doi.org/10.1038/npp.2016.27] [PMID: 26888056]
[48]
Gueye, A.B.; Pryslawsky, Y.; Trigo, J.M.; Poulia, N.; Delis, F.; Antoniou, K.; Loureiro, M.; Laviolette, S.R.; Vemuri, K.; Makriyannis, A.; Le Foll, B. The cb1 neutral antagonist am4113 retains the therapeutic efficacy of the inverse agonist rimonabant for nicotine dependence and weight loss with better psychiatric tolerability. Int. J. Neuropsychopharmacol., 2016, 19(12), 19.
[http://dx.doi.org/10.1093/ijnp/pyw068] [PMID: 27493155]
[49]
Sink, K.S.; Segovia, K.N.; Collins, L.E.; Markus, E.J.; Vemuri, V.K.; Makriyannis, A.; Salamone, J.D. The CB1 inverse agonist AM251, but not the CB1 antagonist AM4113, enhances retention of contextual fear conditioning in rats. Pharmacol. Biochem. Behav., 2010, 95(4), 479-484.
[http://dx.doi.org/10.1016/j.pbb.2010.03.011] [PMID: 20347865]
[50]
Storr, M.A.; Bashashati, M.; Hirota, C.; Vemuri, V.K.; Keenan, C.M.; Duncan, M.; Lutz, B.; Mackie, K.; Makriyannis, A.; Macnaughton, W.K.; Sharkey, K.A. Differential effects of cb(1) neutral antagonists and inverse agonists on gastrointestinal motility in mice. Neurogastroenterol. Motil., 2010, 22, 787-796.
[http://dx.doi.org/DOI: 10.1111/j.1365-2982.2010.01478] [PMID: 20180825]
[51]
Hodge, J.; Bow, J.P.; Plyler, K.S.; Vemuri, V.K.; Wisniecki, A.; Salamone, J.D.; Makriyannis, A.; McLaughlin, P.J. The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats. Behav. Brain Res., 2008, 193(2), 298-305.
[http://dx.doi.org/10.1016/j.bbr.2008.06.010] [PMID: 18602425]
[52]
Tai, S.; Nikas, S.P.; Shukla, V.G.; Vemuri, K.; Makriyannis, A.; Järbe, T.U. Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist. Psychopharmacology (Berl.), 2015, 232(15), 2751-2761.
[http://dx.doi.org/10.1007/s00213-015-3907-0] [PMID: 25772338]
[53]
Sink, K.S.; Vemuri, V.K.; Wood, J.; Makriyannis, A.; Salamone, J.D. Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113. Pharmacol. Biochem. Behav., 2009, 91(3), 303-306.
[http://dx.doi.org/10.1016/j.pbb.2008.07.013] [PMID: 18703081]
[54]
Mastinu, A.; Pira, M.; Pinna, G.A.; Pisu, C.; Casu, M.A.; Reali, R.; Marcello, S.; Murineddu, G.; Lazzari, P. NESS06SM reduces body weight with an improved profile relative to SR141716A. Pharmacol. Res., 2013, 74, 94-108.
[http://dx.doi.org/10.1016/j.phrs.2013.06.001] [PMID: 23756200]
[55]
Lazzari, P.; Serra, V.; Marcello, S.; Pira, M.; Mastinu, A. Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats. Eur. Neuropsychopharmacol., 2017, 27(7), 667-678.
[http://dx.doi.org/10.1016/j.euroneuro.2017.03.010] [PMID: 28377074]
[56]
Goonawardena, A.V.; Plano, A.; Robinson, L.; Ross, R.; Greig, I.; Pertwee, R.G.; Hampson, R.E.; Platt, B.; Riedel, G. Modulation of food consumption and sleep-wake cycle in mice by the neutral CB1 antagonist ABD459. Behav. Pharmacol., 2015, 26(3), 289-303.
[http://dx.doi.org/10.1097/FBP.0000000000000108] [PMID: 25356730]
[57]
Manca, I.; Mastinu, A.; Olimpieri, F.; Falzoi, M.; Sani, M.; Ruiu, S.; Loriga, G.; Volonterio, A.; Tambaro, S.; Bottazzi, M.E.; Zanda, M.; Pinna, G.A.; Lazzari, P. Novel pyrazole derivatives as neutral CB1 antagonists with significant activity towards food intake. Eur. J. Med. Chem., 2013, 62, 256-269.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.056] [PMID: 23357307]
[58]
Boström, J.; Olsson, R.I.; Tholander, J.; Greasley, P.J.; Ryberg, E.; Nordberg, H.; Hjorth, S.; Cheng, L. Novel thioamide derivatives as neutral CB1 receptor antagonists. Bioorg. Med. Chem. Lett., 2010, 20(2), 479-482.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.125] [PMID: 20005704]
[59]
Pertwee, R.G.; Thomas, A.; Stevenson, L.A.; Ross, R.A.; Varvel, S.A.; Lichtman, A.H.; Martin, B.R.; Razdan, R.K. The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo. Br. J. Pharmacol., 2007, 150(5), 586-594.
[http://dx.doi.org/10.1038/sj.bjp.0707124] [PMID: 17245367]
[60]
Bátkai, S.; Mukhopadhyay, P.; Horváth, B.; Rajesh, M.; Gao, R.Y.; Mahadevan, A.; Amere, M.; Battista, N.; Lichtman, A.H.; Gauson, L.A.; Maccarrone, M.; Pertwee, R.G.; Pacher, P.Δ. 8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. Br. J. Pharmacol., 2012, 165(8), 2450-2461.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01410.x] [PMID: 21470208]
[61]
Thomas, A.; Stevenson, L.A.; Wease, K.N.; Price, M.R.; Baillie, G.; Ross, R.A.; Pertwee, R.G. Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br. J. Pharmacol., 2005, 146(7), 917-926.
[http://dx.doi.org/10.1038/sj.bjp.0706414] [PMID: 16205722]
[62]
Bolognini, D.; Costa, B.; Maione, S.; Comelli, F.; Marini, P.; Di Marzo, V.; Parolaro, D.; Ross, R.A.; Gauson, L.A.; Cascio, M.G.; Pertwee, R.G. The plant cannabinoid Delta9-tetrahydro-cannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br. J. Pharmacol., 2010, 160(3), 677-687.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00756.x] [PMID: 20590571]
[63]
Riedel, G.; Fadda, P.; McKillop-Smith, S.; Pertwee, R.G.; Platt, B.; Robinson, L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br. J. Pharmacol., 2009, 156(7), 1154-1166.
[http://dx.doi.org/10.1111/j.1476-5381.2008.00107.x] [PMID: 19378378]
[64]
Wargent, E.T.; Zaibi, M.S.; Silvestri, C.; Hislop, D.C.; Stocker, C.J.; Stott, C.G.; Guy, G.W.; Duncan, M.; Di Marzo, V.; Cawthorne, M.A. The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr. Diabetes, 2013, 3e68
[http://dx.doi.org/10.1038/nutd.2013.9] [PMID: 23712280]
[65]
Tudge, L.; Williams, C.; Cowen, P.J.; McCabe, C. Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers. Int. J. Neuropsychopharmacol., 2014, 18(6), 1-9.
[PMID: 25542687]
[66]
Rzepa, E.; Tudge, L.; McCabe, C. The cb1 neutral antagonist tetrahydrocannabivarin reduces default mode network and increases executive control network resting state functional connectivity in healthy volunteers. Int. J. Neuropsychopharmacol., 2015, 19(2), 1-7.
[PMID: 26362774]
[67]
Thomas, A.; Ross, R.A.; Saha, B.; Mahadevan, A.; Razdan, R.K.; Pertwee, R.G. 6”-Azidohex-2”-yne-cannabidiol: a potential neutral, competitive cannabinoid CB1 receptor antagonist. Eur. J. Pharmacol., 2004, 487(1-3), 213-221.
[http://dx.doi.org/10.1016/j.ejphar.2004.01.023] [PMID: 15033394]
[68]
Wiley, J.L.; Breivogel, C.S.; Mahadevan, A.; Pertwee, R.G.; Cascio, M.G.; Bolognini, D.; Huffman, J.W.; Walentiny, D.M.; Vann, R.E.; Razdan, R.K.; Martin, B.R. Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid CB(1) receptor antagonist. Eur. J. Pharmacol., 2011, 651(1-3), 96-105.
[http://dx.doi.org/10.1016/j.ejphar.2010.10.085] [PMID: 21114999]
[69]
Jergas, B.; Schulte, K.; Bindila, L.; Lutz, B.; Schlicker, E. O-2050 facilitates noradrenaline release and increases the CB1 receptor inverse agonistic effect of rimonabant in the guinea pig hippocampus. Naunyn Schmiedebergs Arch. Pharmacol., 2014, 387(7), 621-628.
[http://dx.doi.org/10.1007/s00210-014-0991-3] [PMID: 24853577]
[70]
Elsebai, M.F.; Rempel, V.; Schnakenburg, G.; Kehraus, S.; Müller, C.E.; König, G.M. Identification of a potent and selective cannabinoid cb1 receptor antagonist from auxarthron reticulatum. ACS Med. Chem. Lett., 2011, 2(11), 866-869.
[http://dx.doi.org/10.1021/ml200183z] [PMID: 24900275]
[71]
Seely, K.A.; Brents, L.K.; Radominska-Pandya, A.; Endres, G.W.; Keyes, G.S.; Moran, J.H.; Prather, P.L. A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors. Chem. Res. Toxicol., 2012, 25(4), 825-827.
[http://dx.doi.org/10.1021/tx3000472] [PMID: 22404317]
[72]
Pajouhesh, H.; Lenz, G.R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2005, 2(4), 541-553.
[http://dx.doi.org/10.1602/neurorx.2.4.541] [PMID: 16489364]
[73]
Kelder, J.; Grootenhuis, P.D.; Bayada, D.M.; Delbressine, L.P.; Ploemen, J.P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res., 1999, 16(10), 1514-1519.
[http://dx.doi.org/10.1023/A:1015040217741] [PMID: 10554091]
[74]
Chorvat, R.J. Peripherally restricted CB1 receptor blockers. Bioorg. Med. Chem. Lett., 2013, 23(17), 4751-4760.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.066] [PMID: 23902803]
[75]
Cluny, N.L.; Vemuri, V.K.; Chambers, A.P.; Limebeer, C.L.; Bedard, H.; Wood, J.T.; Lutz, B.; Zimmer, A.; Parker, L.A.; Makriyannis, A.; Sharkey, K.A. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents. Br. J. Pharmacol., 2010, 161(3), 629-642.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00908.x] [PMID: 20880401]
[76]
Randall, P.A.; Vemuri, V.K.; Segovia, K.N.; Torres, E.F.; Hosmer, S.; Nunes, E.J.; Santerre, J.L.; Makriyannis, A.; Salamone, J.D. The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior. Pharmacol. Biochem. Behav., 2010, 97(1), 179-184.
[http://dx.doi.org/10.1016/j.pbb.2010.07.021] [PMID: 20713079]
[77]
Argueta, D.A.; DiPatrizio, N.V. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol. Behav., 2017, 171, 32-39.
[http://dx.doi.org/10.1016/j.physbeh.2016.12.044] [PMID: 28065722]
[78]
DiPatrizio, N.V.; Igarashi, M.; Narayanaswami, V.; Murray, C.; Gancayco, J.; Russell, A.; Jung, K.M.; Piomelli, D. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2015, 309(8), R805-R813.
[http://dx.doi.org/10.1152/ajpregu.00239.2015] [PMID: 26290104]
[79]
Boon, M.R.; Kooijman, S.; van Dam, A.D.; Pelgrom, L.R.; Berbée, J.F.; Visseren, C.A.; van Aggele, R.C.; van den Hoek, A.M.; Sips, H.C.; Lombès, M.; Havekes, L.M.; Tamsma, J.T.; Guigas, B.; Meijer, O.C.; Jukema, J.W.; Rensen, P.C. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J., 2014, 28(12), 5361-5375.
[http://dx.doi.org/10.1096/fj.13-247643] [PMID: 25154875]
[80]
Ma, H.; Zhang, G.; Mou, C.; Fu, X.; Chen, Y. Peripheral cb1 receptor neutral antagonist, am6545, ameliorates hypometabolic obesity and improves adipokine secretion in monosodium glutamate induced obese mice. Front. Pharmacol., 2018, 9, 156.
[http://dx.doi.org/10.3389/fphar.2018.00156] [PMID: 29615900]
[81]
Bowles, N.P.; Karatsoreos, I.N.; Li, X.; Vemuri, V.K.; Wood, J.A.; Li, Z.; Tamashiro, K.L.; Schwartz, G.J.; Makriyannis, A.M.; Kunos, G.; Hillard, C.J.; McEwen, B.S.; Hill, M.N. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc. Natl. Acad. Sci. USA, 2015, 112(1), 285-290.
[http://dx.doi.org/10.1073/pnas.1421420112] [PMID: 25535367]
[82]
Barutta, F.; Grimaldi, S.; Gambino, R.; Vemuri, K.; Makriyannis, A.; Annaratone, L.; di Marzo, V.; Bruno, G.; Gruden, G. Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy. Nephrol. Dial. Transplant., 2017, 32(10), 1655-1665.
[http://dx.doi.org/10.1093/ndt/gfx010] [PMID: 28387811]
[83]
Grzeda, E.; Schlicker, E.; Luczaj, W.; Harasim, E.; Baranowska-Kuczko, M.; Malinowska, B. Bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids in anaesthetized rats: role of the paraventricular nucleus. J. Physiol. Pharmacol., 2015, 66(3), 343-353.
[PMID: 26084216]
[84]
Bronova, I.; Smith, B.; Aydogan, B.; Weichselbaum, R.R.; Vemuri, K.; Erdelyi, K.; Makriyannis, A.; Pacher, P.; Berdyshev, E.V. Protection from radiation-induced pulmonary fibrosis by peripheral targeting of cannabinoid receptor-1. Am. J. Respir. Cell Mol. Biol., 2015, 53(4), 555-562.
[http://dx.doi.org/10.1165/rcmb.2014-0331OC] [PMID: 26426981]
[85]
Limebeer, C.L.; Vemuri, V.K.; Bedard, H.; Lang, S.T.; Ossenkopp, K.P.; Makriyannis, A.; Parker, L.A. Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats. Br. J. Pharmacol., 2010, 161(2), 336-349.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00885.x] [PMID: 20735419]
[86]
McLaughlin, P.J.; Jagielo-Miller, J.E.; Plyler, E.S.; Schutte, K.K.; Vemuri, V.K.; Makriyannis, A. Differential effects of cannabinoid CB1 inverse agonists and antagonists on impulsivity in male Sprague Dawley rats: identification of a possibly clinically relevant vulnerability involving the serotonin 5HT1A receptor. Psychopharmacology (Berl.), 2017, 234(6), 1029-1043.
[http://dx.doi.org/10.1007/s00213-017-4548-2] [PMID: 28144708]
[87]
7TM_Pharma. (2009). TM38837, a CB1 receptor antagonist/ inverse agonist. Investigator's brochure. 2009.
[88]
Klumpers, L.E.; Fridberg, M.; de Kam, M.L.; Little, P.B.; Jensen, N.O.; Kleinloog, H.D.; Elling, C.E.; van Gerven, J.M. Peripheral selectivity of the novel cannabinoid receptor antagonist TM38837 in healthy subjects. Br. J. Clin. Pharmacol., 2013, 76(6), 846-857.
[http://dx.doi.org/10.1111/bcp.12141] [PMID: 23601084]
[89]
Guan, Z.; Klumpers, L.E.; Oyetayo, O-O.; Heuberger, J.; van Gerven, J.M.; Stevens, J. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests. Br. J. Clin. Pharmacol., 2016, 81(4), 713-723.
[http://dx.doi.org/10.1111/bcp.12852] [PMID: 26617196]
[90]
Takano, A.; Gulyás, B.; Varnäs, K.; Little, P.B.; Noerregaard, P.K.; Jensen, N.O.; Elling, C.E.; Halldin, C. Low brain CB1 receptor occupancy by a second generation CB1 receptor antagonist TM38837 in comparison with rimonabant in nonhuman primates: a PET study. Synapse, 2014, 68(3), 89-97.
[http://dx.doi.org/10.1002/syn.21721] [PMID: 24293119]
[91]
Fulp, A.; Bortoff, K.; Zhang, Y.; Seltzman, H.; Snyder, R.; Maitra, R. Towards rational design of cannabinoid receptor 1 (CB1) antagonists for peripheral selectivity. Bioorg. Med. Chem. Lett., 2011, 21(19), 5711-5714.
[http://dx.doi.org/10.1016/j.bmcl.2011.08.032] [PMID: 21875798]
[92]
Fulp, A.; Bortoff, K.; Seltzman, H.; Zhang, Y.; Mathews, J.; Snyder, R.; Fennell, T.; Maitra, R. Design and synthesis of cannabinoid receptor 1 antagonists for peripheral selectivity. J. Med. Chem., 2012, 55(6), 2820-2834.
[http://dx.doi.org/10.1021/jm201731z] [PMID: 22372835]
[93]
Fulp, A.; Zhang, Y.; Bortoff, K.; Seltzman, H.; Snyder, R.; Wiethe, R.; Amato, G.; Maitra, R. Pyrazole antagonists of the CB1 receptor with reduced brain penetration. Bioorg. Med. Chem., 2016, 24(5), 1063-1070.
[http://dx.doi.org/10.1016/j.bmc.2016.01.033] [PMID: 26827137]
[94]
Tai, C.L.; Hung, M.S.; Pawar, V.D.; Tseng, S.L.; Song, J.S.; Hsieh, W.P.; Chiu, H.H.; Wu, H.C.; Hsieh, M.T.; Kuo, C.W.; Hsieh, C.C.; Tsao, J.P.; Chao, Y.S.; Shia, K.S. Design, synthesis, and biological evaluation of novel alkenylthiophenes as potent and selective CB1 cannabinoid receptor antagonists. Org. Biomol. Chem., 2008, 6(3), 447-450.
[http://dx.doi.org/10.1039/B716434C] [PMID: 18219411]
[95]
Hung, M.S.; Chang, C.P.; Li, T.C.; Yeh, T.K.; Song, J.S.; Lin, Y.; Wu, C.H.; Kuo, P.C.; Amancha, P.K.; Wong, Y.C.; Hsiao, W.C.; Chao, Y.S.; Shia, K.S. Discovery of 1-(2,4-dichlorophenyl)-4-ethyl-5-(5-(2-(4-(trifluoromethyl)phenyl)ethynyl)thiophen-2-yl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide as a potential peripheral cannabinoid-1 receptor inverse agonist. ChemMedChem, 2010, 5(9), 1439-1443.
[http://dx.doi.org/10.1002/cmdc.201000246] [PMID: 20652930]
[96]
Chang, C.P.; Wu, C.H.; Song, J.S.; Chou, M.C.; Wong, Y.C.; Lin, Y.; Yeh, T.K.; Sadani, A.A.; Ou, M.H.; Chen, K.H.; Chen, P.H.; Kuo, P.C.; Tseng, C.T.; Chang, K.H.; Tseng, S.L.; Chao, Y.S.; Hung, M.S.; Shia, K.S. Discovery of 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced obese mice. J. Med. Chem., 2013, 56(24), 9920-9933.
[http://dx.doi.org/10.1021/jm401158e] [PMID: 24224693]
[97]
Chen, W.; Shui, F.; Liu, C.; Zhou, X.; Li, W.; Zheng, Z.; Fu, W.; Wang, L. Novel peripherally restricted cannabinoid 1 receptor selective antagonist txx-522 with prominent weight-loss efficacy in diet induced obese mice. Front. Pharmacol., 2017, 8, 707.
[http://dx.doi.org/10.3389/fphar.2017.00707] [PMID: 29051736]
[98]
Jagerovic, N.; Hernandez-Folgado, L.; Alkorta, I.; Goya, P.; Navarro, M.; Serrano, A.; Rodriguez de Fonseca, F.; Dannert, M.T.; Alsasua, A.; Suardiaz, M.; Pascual, D.; Martín, M.I. Discovery of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1h-1,2,4-triazole, a novel in vivo cannabinoid antagonist containing a 1,2,4-triazole motif. J. Med. Chem., 2004, 47(11), 2939-2942.
[http://dx.doi.org/10.1021/jm031099y] [PMID: 15139773]
[99]
Chen, R.Z.; Frassetto, A.; Lao, J.Z.; Huang, R.R.; Xiao, J.C.; Clements, M.J.; Walsh, T.F.; Hale, J.J.; Wang, J.; Tong, X.; Fong, T.M. Pharmacological evaluation of LH-21, a newly discovered molecule that binds to cannabinoid CB1 receptor. Eur. J. Pharmacol., 2008, 584(2-3), 338-342.
[http://dx.doi.org/10.1016/j.ejphar.2008.02.029] [PMID: 18336811]
[100]
Alen, F.; Crespo, I.; Ramírez-López, M.T.; Jagerovic, N.; Goya, P.; de Fonseca, F.R.; de Heras, R.G.; Orio, L. Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism. PLoS One, 2013, 8(4)e60918
[http://dx.doi.org/10.1371/journal.pone.0060918] [PMID: 23565287]
[101]
Romero-Zerbo, S.Y.; Ruz-Maldonado, I.; Espinosa-Jiménez, V.; Rafacho, A.; Gómez-Conde, A.I.; Sánchez-Salido, L.; Cobo-Vuilleumier, N.; Gauthier, B.R.; Tinahones, F.J.; Persaud, S.J.; Bermúdez-Silva, F.J. The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice. Sci. Rep., 2017, 7(1), 3946.
[http://dx.doi.org/10.1038/s41598-017-03292-w] [PMID: 28638091]
[102]
Pavón, F.J.; Serrano, A.; Pérez-Valero, V.; Jagerovic, N.; Hernández-Folgado, L.; Bermúdez-Silva, F.J.; Macías, M.; Goya, P.; de Fonseca, F.R. Central versus peripheral antagonism of cannabinoid CB1 receptor in obesity: effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist, in Zucker rats. J. Neuroendocrinol., 2008, 20(Suppl. 1), 116-123.
[http://dx.doi.org/10.1111/j.1365-2826.2008.01693.x] [PMID: 18426510]
[103]
Alonso, M.; Serrano, A.; Vida, M.; Crespillo, A.; Hernandez-Folgado, L.; Jagerovic, N.; Goya, P.; Reyes-Cabello, C.; Perez-Valero, V.; Decara, J.; Macías-González, M.; Bermúdez-Silva, F.J.; Suárez, J.; Rodríguez de Fonseca, F.; Pavón, F.J. Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats. Br. J. Pharmacol., 2012, 165(7), 2274-2291.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01698.x] [PMID: 21951309]
[104]
Pavon, F.J.; Bilbao, A.; Hernández-Folgado, L.; Cippitelli, A.; Jagerovic, N.; Abellán, G.; Rodríguez-Franco, M.A.; Serrano, A.; Macias, M.; Gómez, R.; Navarro, M.; Goya, P.; Rodríguez de Fonseca, F. Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21. Neuropharmacology, 2006, 51(2), 358-366.
[http://dx.doi.org/10.1016/j.neuropharm.2006.03.029] [PMID: 16750544]
[105]
Chorvat, R.J.; Berbaum, J.; Seriacki, K.; McElroy, J.F. JD-5006 and JD-5037: peripherally restricted (PR) cannabinoid-1 receptor blockers related to SLV-319 (Ibipinabant) as metabolic disorder therapeutics devoid of CNS liabilities. Bioorg. Med. Chem. Lett., 2012, 22(19), 6173-6180.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.004] [PMID: 22959249]
[106]
Chorvat, R.J. Jenrin discovery’s IND application for its peripherally restricted cannabinoid-1 receptor inverse agonist nash compound was cleared by the FDA to begin phase 1 clinical trials., 2017. (Accessed Sep 2018 at: https://www.businesswire.com/news/home/20171214005128/en/Jenrin-Discovery%E2%80%99s-IND-Application-Peripherally-Restricted-Cannabinoid-1.
[107]
Jourdan, T.; Szanda, G.; Rosenberg, A.Z.; Tam, J.; Earley, B.J.; Godlewski, G.; Cinar, R.; Liu, Z.; Liu, J.; Ju, C.; Pacher, P.; Kunos, G. Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc. Natl. Acad. Sci. USA, 2014, 111(50), E5420-E5428.
[http://dx.doi.org/10.1073/pnas.1419901111] [PMID: 25422468]
[108]
Mukhopadhyay, B.; Schuebel, K.; Mukhopadhyay, P.; Cinar, R.; Godlewski, G.; Xiong, K.; Mackie, K.; Lizak, M.; Yuan, Q.; Goldman, D.; Kunos, G. Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. Hepatology, 2015, 61(5), 1615-1626.
[http://dx.doi.org/10.1002/hep.27686] [PMID: 25580584]
[109]
Tam, J.; Cinar, R.; Liu, J.; Godlewski, G.; Wesley, D.; Jourdan, T.; Szanda, G.; Mukhopadhyay, B.; Chedester, L.; Liow, J.S.; Innis, R.B.; Cheng, K.; Rice, K.C.; Deschamps, J.R.; Chorvat, R.J.; McElroy, J.F.; Kunos, G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab., 2012, 16(2), 167-179.
[http://dx.doi.org/10.1016/j.cmet.2012.07.002] [PMID: 22841573]
[110]
Cinar, R.; Godlewski, G.; Liu, J.; Tam, J.; Jourdan, T.; Mukhopadhyay, B.; Harvey-White, J.; Kunos, G. Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides. Hepatology, 2014, 59(1), 143-153.
[http://dx.doi.org/10.1002/hep.26606] [PMID: 23832510]
[111]
Tam, J.; Szanda, G.; Drori, A.; Liu, Z.; Cinar, R.; Kashiwaya, Y.; Reitman, M.L.; Kunos, G. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol. Metab., 2017, 6(10), 1113-1125.
[http://dx.doi.org/10.1016/j.molmet.2017.06.010] [PMID: 29031713]
[112]
Knani, I.; Earley, B.J.; Udi, S.; Nemirovski, A.; Hadar, R.; Gammal, A.; Cinar, R.; Hirsch, H.J.; Pollak, Y.; Gross, I.; Eldar-Geva, T.; Reyes-Capo, D.P.; Han, J.C.; Haqq, A.M.; Gross-Tsur, V.; Wevrick, R.; Tam, J. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome. Mol. Metab., 2016, 5(12), 1187-1199.
[http://dx.doi.org/10.1016/j.molmet.2016.10.004] [PMID: 27900261]
[113]
González-Mariscal, I.; Krzysik-Walker, S.M.; Doyle, M.E.; Liu, Q.R.; Cimbro, R.; Santa-Cruz Calvo, S.; Ghosh, S.; Cieśla, Ł.; Moaddel, R.; Carlson, O.D.; Witek, R.P.; O’Connell, J.F.; Egan, J.M. Human cb1 receptor isoforms, present in hepatocytes and beta-cells, are involved in regulating metabolism. Sci. Rep., 2016, 6, 33302.
[http://dx.doi.org/10.1038/srep33302] [PMID: 27641999]
[114]
Griffith, D.A.; Hadcock, J.R.; Black, S.C.; Iredale, P.A.; Carpino, P.A.; DaSilva-Jardine, P.; Day, R.; DiBrino, J.; Dow, R.L.; Landis, M.S.; O’Connor, R.E.; Scott, D.O. Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylaminopiperidine-4-carboxylic acid amide hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist. J. Med. Chem., 2009, 52(2), 234-237.
[http://dx.doi.org/10.1021/jm8012932] [PMID: 19102698]
[115]
Fulp, A.; Bortoff, K.; Zhang, Y.; Seltzman, H.; Mathews, J.; Snyder, R.; Fennell, T.; Maitra, R. Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists. J. Med. Chem., 2012, 55(22), 10022-10032.
[http://dx.doi.org/10.1021/jm301181r] [PMID: 23098108]
[116]
Fulp, A.; Bortoff, K.; Zhang, Y.; Snyder, R.; Fennell, T.; Marusich, J.A.; Wiley, J.L.; Seltzman, H.; Maitra, R. Peripherally selective diphenyl purine antagonist of the CB1 receptor. J. Med. Chem., 2013, 56(20), 8066-8072.
[http://dx.doi.org/10.1021/jm401129n] [PMID: 24041123]
[117]
Amato, G.S.; Manke, A.; Harris, D.L.; Wiethe, R.W.; Vasukuttan, V.; Snyder, R.W.; Lefever, T.W.; Cortes, R.; Zhang, Y.; Wang, S.; Runyon, S.P.; Maitra, R. Blocking alcoholic steatosis in mice with a peripherally restricted purine antagonist of the type 1 cannabinoid receptor. J. Med. Chem., 2018, 61(10), 4370-4385.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01820] [PMID: 29688015]
[118]
Amato, G.S.; Manke, A.; Vasukuttan, V.; Wiethe, R.W.; Snyder, R.W.; Runyon, S.P.; Maitra, R. Synthesis and pharmacological characterization of functionalized 6-piperazin-1-yl-purines as cannabinoid receptor 1 (CB1) inverse agonists. Bioorg. Med. Chem., 2018, 26(15), 4518-4531.
[http://dx.doi.org/10.1016/j.bmc.2018.07.043] [PMID: 30077609]
[119]
Picone, R.P.; Khanolkar, A.D.; Xu, W.; Ayotte, L.A.; Thakur, G.A.; Hurst, D.P.; Abood, M.E.; Reggio, P.H.; Fournier, D.J.; Makriyannis, A. (-)-7′-Isothiocyanato-11-hydroxy-1′,1′-dimethyl-heptylhexahydrocannabinol (AM841), a high-affinity electrophilic ligand, interacts covalently with a cysteine in helix six and activates the CB1 cannabinoid receptor. Mol. Pharmacol., 2005, 68(6), 1623-1635.
[PMID: 16157695]
[120]
Keenan, C.M.; Storr, M.A.; Thakur, G.A.; Wood, J.T.; Wager-Miller, J.; Straiker, A.; Eno, M.R.; Nikas, S.P.; Bashashati, M.; Hu, H.; Mackie, K.; Makriyannis, A.; Sharkey, K.A. AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner. Br. J. Pharmacol., 2015, 172(9), 2406-2418.
[http://dx.doi.org/10.1111/bph.13069] [PMID: 25572435]
[121]
Zhu, B.; Matthews, J.M.; Xia, M.; Black, S.; Chen, C.; Hou, C.; Liang, Y.; Tang, Y.; Macielag, M.J. Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists. Bioorg. Med. Chem. Lett., 2016, 26(22), 5597-5601.
[http://dx.doi.org/10.1016/j.bmcl.2016.09.026] [PMID: 27671499]
[122]
Matthews, J.M.; McNally, J.J.; Connolly, P.J.; Xia, M.; Zhu, B.; Black, S.; Chen, C.; Hou, C.; Liang, Y.; Tang, Y.; Macielag, M.J. Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists. Bioorg. Med. Chem. Lett., 2016, 26(21), 5346-5349.
[http://dx.doi.org/10.1016/j.bmcl.2016.09.025] [PMID: 27671496]
[123]
Price, M.R.; Baillie, G.L.; Thomas, A.; Stevenson, L.A.; Easson, M.; Goodwin, R.; McLean, A.; McIntosh, L.; Goodwin, G.; Walker, G.; Westwood, P.; Marrs, J.; Thomson, F.; Cowley, P.; Christopoulos, A.; Pertwee, R.G.; Ross, R.A. Allosteric modulation of the cannabinoid CB1 receptor. Mol. Pharmacol., 2005, 68(5), 1484-1495.
[http://dx.doi.org/10.1124/mol.105.016162] [PMID: 16113085]
[124]
Conn, P.J.; Christopoulos, A.; Lindsley, C.W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov., 2009, 8(1), 41-54.
[http://dx.doi.org/10.1038/nrd2760] [PMID: 19116626]
[125]
Kenakin, T.; Strachan, R.T. Pam-antagonists: A better way to block pathological receptor signaling? Trends Pharmacol. Sci., 2018, 39(8), 748-765.
[http://dx.doi.org/10.1016/j.tips.2018.05.001] [PMID: 29885909]
[126]
Nguyen, T.; Li, J.X.; Thomas, B.F.; Wiley, J.L.; Kenakin, T.P.; Zhang, Y. Allosteric modulation: An alternate approach targeting the cannabinoid cb1 receptor. Med. Res. Rev., 2017, 37(3), 441-474.
[http://dx.doi.org/10.1002/med.21418] [PMID: 27879006]
[127]
Khajehali, E.; Malone, D.T.; Glass, M.; Sexton, P.M.; Christopoulos, A.; Leach, K. Biased agonism and biased allosteric modulation at the cb1 cannabinoid receptor. Mol. Pharmacol., 2015, 88(2), 368-379.
[http://dx.doi.org/10.1124/mol.115.099192] [PMID: 26044547]
[128]
Baillie, G.L.; Horswill, J.G.; Anavi-Goffer, S.; Reggio, P.H.; Bolognini, D.; Abood, M.E.; McAllister, S.; Strange, P.G.; Stephens, G.J.; Pertwee, R.G.; Ross, R.A. CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. Mol. Pharmacol., 2013, 83(2), 322-338.
[http://dx.doi.org/10.1124/mol.112.080879] [PMID: 23160940]
[129]
Nguyen, T.; German, N.; Decker, A.M.; Li, J.X.; Wiley, J.L.; Thomas, B.F.; Kenakin, T.P.; Zhang, Y. Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators. Bioorg. Med. Chem., 2015, 23(9), 2195-2203.
[http://dx.doi.org/10.1016/j.bmc.2015.02.058] [PMID: 25797163]
[130]
Piscitelli, F.L. Alessia; La Regina, Giuseppe; Coluccia, Antonio; Morera, Ludovica; Allara, Marco; Novellino, Ettore; Di Marzo, Vincenzo; Silvestri, Romano. Indole-2-carboxamides as allosteric modulators of the cannabinoid cb1 receptor. J. Med. Chem., 2012, 55, 5627-5631.
[http://dx.doi.org/10.1021/jm201485c] [PMID: 22571451]
[131]
Ahn, K.H.; Mahmoud, M.M.; Samala, S.; Lu, D.; Kendall, D.A. Profiling two indole-2-carboxamides for allosteric modulation of the CB1 receptor. J. Neurochem., 2013, 124(5), 584-589.
[http://dx.doi.org/10.1111/jnc.12115] [PMID: 23205875]
[132]
Greig, I.R.; Ross, R.A.; Pertwee, R.G.; Trembleau, L.; Abdelrahman, M.; Baillie, G.L.N. N-(arylalkyl)-1h-indole-2-sulfonic acid amide compounds and their therapeutic use as cannabinoid allosteric modulators. Greater Britain Patent WO 2012/117216 A1, Sep 7 2012.
[133]
Khurana, L.; Ali, H.I.; Olszewska, T.; Ahn, K.H.; Damaraju, A.; Kendall, D.A.; Lu, D. Optimization of chemical functionalities of indole-2-carboxamides to improve allosteric parameters for the cannabinoid receptor 1 (CB1). J. Med. Chem., 2014, 57(7), 3040-3052.
[http://dx.doi.org/10.1021/jm5000112] [PMID: 24635495]
[134]
Gamage, T.F.; Ignatowska-Jankowska, B.M.; Wiley, J.L.; Abdelrahman, M.; Trembleau, L.; Greig, I.R.; Thakur, G.A.; Tichkule, R.; Poklis, J.; Ross, R.A.; Pertwee, R.G.; Lichtman, A.H. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav. Pharmacol., 2014, 25(2), 182-185.
[http://dx.doi.org/10.1097/FBP.0000000000000027] [PMID: 24603340]
[135]
Ding, Y.; Qiu, Y.; Jing, L.; Thorn, D.A.; Zhang, Y.; Li, J.X. Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. Pharmacol. Res. Perspect., 2014, 2(6)e00069
[http://dx.doi.org/10.1002/prp2.69] [PMID: 25431655]
[136]
German, N.; Decker, A.M.; Gilmour, B.P.; Gay, E.A.; Wiley, J.L.; Thomas, B.F.; Zhang, Y. 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]phe-nylurea (psncbam-1). J. Med. Chem., 2014, 57, 7758-7769.
[http://dx.doi.org/10.1021/jm501042u] [PMID: 25162172]
[137]
Thakur, G.A.; Kulkarni, P.M. Allosteric modulators of CB1 cannabinoid receptors. United States. Patent US 2015/0005346 A1, Assignee: Northeastern University., 2015.
[138]
Nguyen, T.; German, N.; Decker, A.M.; Langston, T.L.; Gamage, T.F.; Farquhar, C.E.; Li, J.X.; Wiley, J.L.; Thomas, B.F.; Zhang, Y. Novel diarylurea based allosteric modulators of the cannabinoid cb1 receptor: Evaluation of importance of 6-pyrrolidinylpyridinyl substitution. J. Med. Chem., 2017, 60(17), 7410-7424.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00707] [PMID: 28792219]
[139]
Khurana, L.; Fu, B.Q.; Duddupudi, A.L.; Liao, Y.H.; Immadi, S.S.; Kendall, D.A.; Lu, D. Pyrimidinyl biphenylureas: Identification of new lead compounds as allosteric modulators of the cannabinoid receptor cb1. J. Med. Chem., 2017, 60(3), 1089-1104.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01448] [PMID: 28059509]
[140]
Bertini, S.; Chicca, A.; Gado, F.; Arena, C.; Nieri, D.; Digiacomo, M.; Saccomanni, G.; Zhao, P.; Abood, M.E.; Macchia, M.; Gertsch, J.; Manera, C. Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor. Bioorg. Med. Chem., 2017, 25(24), 6427-6434.
[http://dx.doi.org/10.1016/j.bmc.2017.10.015] [PMID: 29079014]
[141]
Nguyen, T.; Gamage, T.F.; Decker, A.M.; German, N.; Langston, T.L.; Farquhar, C.E.; Kenakin, T.P.; Wiley, J.L.; Thomas, B.F.; Zhang, Y. Diarylureas containing 5-membered heterocycles as cb1 receptor allosteric modulators: Design, synthesis, and pharmacological evaluation. ACS Chem. Neurosci., 2019, 10(1), 518-527.
[http://dx.doi.org/10.1021/acschemneuro.8b00396] [PMID: 30188693]
[142]
Gamage, T.F.; Farquhar, C.E.; Lefever, T.W.; Thomas, B.F.; Nguyen, T.; Zhang, Y.; Wiley, J.L. The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB1 receptor allosteric modulators. Neuropharmacology, 2017, 125, 365-375.
[http://dx.doi.org/10.1016/j.neuropharm.2017.08.008] [PMID: 28803965]
[143]
Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.; Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch, J. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem., 2012, 287(44), 36944-36967.
[http://dx.doi.org/10.1074/jbc.M112.382481] [PMID: 22952224]
[144]
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., 2015, 99, 370-376.
[http://dx.doi.org/10.1016/j.phrs.2015.07.017] [PMID: 26211948]
[145]
Gomes, I.; Grushko, J.S.; Golebiewska, U.; Hoogendoorn, S.; Gupta, A.; Heimann, A.S.; Ferro, E.S.; Scarlata, S.; Fricker, L.D.; Devi, L.A. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J., 2009, 23(9), 3020-3029.
[http://dx.doi.org/10.1096/fj.09-132142] [PMID: 19380512]
[146]
Petrucci, V.; Chicca, A.; Viveros-Paredes, J.; Gertsch, J. Peptide endocannabinoids (Pepcans) are PAMs of CB2 receptors and involved in the innate immune response. Proceedings of the 24th annual symposiums on the cannabinoids, Research Triangle Park, NC, USA. Publisher: International Cannabinoid Research Society. 2014.
[147]
Vallée, M.; Vitiello, S.; Bellocchio, L.; Hébert-Chatelain, E.; Monlezun, S.; Martin-Garcia, E.; Kasanetz, F.; Baillie, G.L.; Panin, F.; Cathala, A.; Roullot-Lacarrière, V.; Fabre, S.; Hurst, D.P.; Lynch, D.L.; Shore, D.M.; Deroche-Gamonet, V.; Spampinato, U.; Revest, J.M.; Maldonado, R.; Reggio, P.H.; Ross, R.A.; Marsicano, G.; Piazza, P.V. Pregnenolone can protect the brain from cannabis intoxication. Science, 2014, 343(6166), 94-98.
[http://dx.doi.org/10.1126/science.1243985] [PMID: 24385629]
[148]
Priestley, R.S.; Nickolls, S.A.; Alexander, S.P.; Kendall, D.A. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate. FASEB J., 2015, 29(4), 1446-1455.
[http://dx.doi.org/10.1096/fj.14-263053] [PMID: 25550466]
[149]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.; Dupré, D.J.; Denovan-Wright, E.M. Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons. J. Biol. Chem., 2014, 289(36), 24845-24862.
[http://dx.doi.org/10.1074/jbc.M114.557025] [PMID: 25037227]
[150]
Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.; Denovan-Wright, E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol., 2015, 172(20), 4790-4805.
[http://dx.doi.org/10.1111/bph.13250] [PMID: 26218440]
[151]
Salamone, J.D.; McLaughlin, P.J.; Sink, K.; Makriyannis, A.; Parker, L.A. Cannabinoid CB1 receptor inverse agonists and neutral antagonists: effects on food intake, food-reinforced behavior and food aversions. Physiol. Behav., 2007, 91(4), 383-388.
[http://dx.doi.org/10.1016/j.physbeh.2007.04.013] [PMID: 17521686]
[152]
Kenakin, T. Efficacy as a vector: the relative prevalence and paucity of inverse agonism. Mol. Pharmacol., 2004, 65(1), 2-11.
[http://dx.doi.org/10.1124/mol.65.1.2] [PMID: 14722230]
[153]
Giraldo, J. How inverse can a neutral antagonist be? Strategic questions after the rimonabant issue. Drug Discov. Today, 2010, 15(11-12), 411-415.
[http://dx.doi.org/10.1016/j.drudis.2010.04.004] [PMID: 20447467]
[154]
Nissen, S.E.; Nicholls, S.J.; Wolski, K.; Rodés-Cabau, J.; Cannon, C.P.; Deanfield, J.E.; Després, J.P.; Kastelein, J.J.; Steinhubl, S.R.; Kapadia, S.; Yasin, M.; Ruzyllo, W.; Gaudin, C.; Job, B.; Hu, B.; Bhatt, D.L.; Lincoff, A.M.; Tuzcu, E.M.; Investigators, S. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA, 2008, 299(13), 1547-1560.
[http://dx.doi.org/10.1001/jama.299.13.1547] [PMID: 18387931]
[155]
Sugamura, K.; Sugiyama, S.; Nozaki, T.; Matsuzawa, Y.; Izumiya, Y.; Miyata, K.; Nakayama, M.; Kaikita, K.; Obata, T.; Takeya, M.; Ogawa, H. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation, 2009, 119(1), 28-36.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.108.811992] [PMID: 19103987]
[156]
Izzo, A.A.; Camilleri, M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut, 2008, 57(8), 1140-1155.
[http://dx.doi.org/10.1136/gut.2008.148791] [PMID: 18397936]
[157]
Richardson, D.; Pearson, R.G.; Kurian, N.; Latif, M.L.; Garle, M.J.; Barrett, D.A.; Kendall, D.A.; Scammell, B.E.; Reeve, A.J.; Chapman, V. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res. Ther., 2008, 10(2), R43.
[http://dx.doi.org/10.1186/ar2401] [PMID: 18416822]

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