Characterization of a Cannabinoid CB2 Receptor-Selective Agonist, A-836339 [2,2,3,3-Tetramethyl-cyclopropanecarboxylic Acid [3-(2-Methoxy-ethyl)-4,5-dimethyl-3 H-thiazol-(2 Z)-ylidene]-amide], Using in Vitro Pharmacological Assays, in Vivo Pain Models, and Pharmacological Magnetic Resonance Imaging
Abstract
Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB(2) agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB(1) receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tolerance failed to develop following repeated administration of the CB2-specific agonist A-836339.
“Tolerance, a feature which may contribute to loss of analgesic efficacy of currently available analgesics, failed to develop following repeated administration the CB2-specific agonist of A-836339.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [51]
CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to existing treatments.
“Thus, CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to exisiting treatments.51”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [51]
Cites
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Bennett, G. J., & Xie, Y.-K. (1988) · Pain · doi:10.1016/0304-3959(88)90209-6 · Cited by 5,376 · see citing works
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Hargreaves, K., Dubner, R. A., Brown, F. J., Flores, C., & Joris, J. L. (1988) · Pain · doi:10.1016/0304-3959(88)90026-7 · Cited by 5,155 · see citing works
Molecular characterization of a peripheral receptor for cannabinoids
Munro, S., Thomas, K. L., & Abu-Shaar, M. (1993) · Nature · doi:10.1038/365061a0 · Cited by 5,092 · see citing works
Structure of a cannabinoid receptor and functional expression of the cloned cDNA
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C., & Bonner, T. I. (1990) · Nature · doi:10.1038/346561a0 · Cited by 5,011 · see citing works
Galiègue, S., Mary, S., Marchand, J., Dussossoy, D., Carrière, D., Carayon, P., Bouaboula, M., Shire, D. J., Fur, G. L., & Casellas, P. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20780.x · Cited by 1,751 · see citing works
Characterization of a rat model of incisional pain
Brennan, T. J., Vandermeulen, E., & Gebhart, G. F. (1996) · Pain · doi:10.1016/0304-3959(95)01441-1 · Cited by 1,101 · see citing works
Felder, C., Joyce, K. E., Briley, E. M., Mansouri, J., Mackie, K., Blond, O., Lai, Y., Ma, A. L., & Mitchell, R. (1995) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10492-6 · Cited by 900 · see citing works
HU-308: A specific agonist for CB 2 , a peripheral cannabinoid receptor
Hanus, L. O., Breuer, A., Tchilibon, S., Shiloah, S., Goldenberg, D., Horowitz, M., Pertwee, R. G., Ross, R. A., Mechoulam, R., & Fride, E. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.25.14228 · Cited by 574 · see citing works
Ibrahim, M. M., Porreca, F., Lai, J., Albrecht, P. J., Rice, F. L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T. W., Mata, H. P., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409888102 · Cited by 521 · see citing works
Guindon, J., & Hohmann, A. G. (2008) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707531 · Cited by 423 · see citing works
Zhang, J., Hoffert, C., Vu, H. K., Groblewski, T., Ahmad, S., & O'Donnell, D. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02704.x · Cited by 419 · see citing works
CB2 cannabinoid receptor-mediated peripheral antinociception
Malan, P. T., Ibrahim, M. M., Deng, H., Liu, Q., Mata, H. P., Vanderah, T., Porreca, F., & Makriyannis, A. (2001) · Pain · doi:10.1016/s0304-3959(01)00321-9 · Cited by 391 · see citing works
Fox, A., Kesingland, A., Gentry, C., McNair, K., Patel, S., Urban, L., & James, I. (2001) · Pain · doi:10.1016/s0304-3959(00)00474-7 · Cited by 379 · see citing works
Valenzano, K. J., Tafesse, L., Lee, G., Harrison, J. E., Boulet, J. M., Gottshall, S. L., Mark, L., Pearson, M. S., Miller, W., Shan, S., et al. (2005) · Neuropharmacology · doi:10.1016/j.neuropharm.2004.12.008 · Cited by 288 · see citing works
Russo, E. B., Guy, G. W., & Robson, P. (2007) · Chemistry & Biodiversity · doi:10.1002/cbdv.200790150 · Cited by 228 · see citing works
Molecular cloning, expression and function of the murine CB2 peripheral cannabinoid receptor
Shire, D. J., Calandra, B., Rinaldi, M. L., Oustric, D., Pessègue, B., Bonnin, O., Fur, G. L., Caput, D., & Ferrara, P. (1996) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/0167-4781(96)00047-4 · Cited by 208 · see citing works
Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase.
Slipetz, D. M., O’Neill, G. P., Favreau, L., Dufresne, C., Gallant, M., Gareau, Y., Guay, D., Labelle, M., & Metters, K. M. (1995) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)10254-x · Cited by 191 · see citing works
CB2 cannabinoid receptor mediation of antinociception
Ibrahim, M. M., Rude, M. L., Stagg, N. J., Mata, H. P., Lai, J. Y., Vanderah, T. W., Porreca, F., Buckley, N. E., Makriyannis, A., & Malan, P. T. (2006) · Pain · doi:10.1016/j.pain.2005.12.018 · Cited by 172 · see citing works
Yao, B. B., Hsieh, G. C., Frost, J. M., Fan, Y., Garrison, T. R., Daza, A. V., Grayson, G. K., Zhu, C. Z., Pai, M., Chandran, P., et al. (2008) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707568 · Cited by 140 · see citing works
Self-citationCannabimimetic lndoles, Pyrroles and lndenes
Huffman, J. W. (1999) · Current Medicinal Chemistry · doi:10.2174/0929867306666220401125055 · Cited by 134 · see citing works
Hohmann, A. G., Farthing, J. N., Zvonok, A. M., & Makriyannis, A. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.060079 · Cited by 123 · see citing works
Cannabimimetic indoles, pyrroles and indenes.
Huffman, J. W. (1999) · PubMed · Cited by 123 · see citing works
Giblin, G. M. P., O’Shaughnessy, C. T., Naylor, A., Mitchell, W. L., Eatherton, A. J., Slingsby, B. P., Rawlings, D. A., Goldsmith, P., Brown, A. J., Haslam, C. P., et al. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm061195+ · Cited by 121 · see citing works
Yao, B. B., Mukherjee, S., Fan, Y., Garrison, T. R., Daza, A. V., Grayson, G. K., Hooker, B. A., Dart, M. J., Sullivan, J. P., & Meyer, M. D. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706838 · Cited by 118 · see citing works
Self-citationAge-Dependent Opioid Escalation in Chronic Pain Patients
Buntin-Mushock, C., Phillip, L., Moriyama, K., & Pierce, P. A. (2005) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000152191.29311.9b · Cited by 104 · see citing works
Joshi, S. K., Hernandez, G., Mikusa, J. P., Zhu, C. Z., Zhong, C., Salyers, A. K., Wismer, C. T., Chandran, P., Decker, M. W., & Honoré, P. H. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.08.005 · Cited by 100 · see citing works
Self-citationNew class of potent ligands for the human peripheral cannabinoid receptor
Gallant, M., Dufresne, C., Gareau, Y., Guay, D., Leblanc, Y., Prasit, P., Rochette, C., Sawyer, N., Slipetz, D. M., Tremblay, N. M., et al. (1996) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/0960-894x(96)00426-x · Cited by 97 · see citing works
Elmes, S. J. R., Winyard, L. A., Medhurst, S. J., Clayton, N. M., Wilson, A. W., Kendall, D. A., & Chapman, V. (2005) · Pain · doi:10.1016/j.pain.2005.09.005 · Cited by 97 · see citing works
Chin, C.-L., Tovcimak, A. E., Hradil, V. P., Seifert, T. R., Hollingsworth, P. R., Chandran, P., Zhu, C. Z., Gauvin, D. M., Pai, M., Wetter, J. B., et al. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707506 · Cited by 96 · see citing works
Self-citationWhiteside, G. T., Gottshall, S. L., Boulet, J. M., Chaffer, S. M., Harrison, J., Pearson, M. S., Turchin, P. I., Mark, L., Garrison, A. E., & Valenzano, K. J. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.10.043 · Cited by 94 · see citing works
Bingham, B., JONES, P. G., Uveges, A. J., Kotnis, S., Lu, P., Smith, V. A., Sun, S., Resnick, L., Chlenov, M., He, Y., et al. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707303 · Cited by 93 · see citing works
Yamamoto, W., Mikami, T., & Iwamura, H. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.010 · Cited by 89 · see citing works
Novel, Not Adenylyl Cyclase-Coupled Cannabinoid Binding Site in Cerebellum of Mice
Monory, K., Tzavara, E. T., Lexime, J., Ledent, C. A., Parmentier, M., Borsodi, A. D., & Hanoune, J. (2002) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2002.6635 · Cited by 75 · see citing works
Contet, C., Filliol, D., Matifas, A., & Kieffer, B. L. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.10.015 · Cited by 68 · see citing works
Therapeutic potential of cannabinoid receptor agonists as analgesic agents
Fox, A., & Bevan, S. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.6.695 · Cited by 60 · see citing works
Ohta, H., Ishizaka, T., Tatsuzuki, M., Yoshinaga, M., Iida, I., Yamaguchi, T., Tomishima, Y., Futaki, N., Toda, Y., & Saito, S. (2007) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2007.10.087 · Cited by 44 · see citing works
Interventional Approaches to Pain Management
Markman, J. D., & Philip, A. G. (2007) · Medical Clinics of North America · doi:10.1016/j.mcna.2006.10.015 · Cited by 35 · see citing works
McGaraughty, S., Chu, K. L., Dart, M. J., Yao, B. B., & Meyer, M. D. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2008.11.015 · Cited by 31 · see citing works
Self-citationDuncan, M., Kendall, D. A., & Ralevic, V. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.067587 · Cited by 23 · see citing works
Interventional Approaches to Pain Management
Markman, J. D., & Philip, A. G. (2007) · Anesthesiology Clinics · doi:10.1016/j.anclin.2007.07.012 · Cited by 19 · see citing works
New pharmacological strategies for pain relief
Gillen, C., & Maul, C. (2002) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.2.5.691 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
CB2: a cannabinoid receptor with an identity crisis
Atwood, B. K., & Mackie, K. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00729.x · Cited by 633 · see citing works
“Keratinocytes release beta-endorphin in response to CB2 selective agonist stimulation (Ibrahim et al., 2005), although this result is controversial (Whiteside et al., 2007; Anand et al., 2008; Yao et al., 2008; Yao et al., 2009).”
BackgroundInfluentialCannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside
Rahn, E. J., & Hohmann, A. G. (2009) · Neurotherapeutics · doi:10.1016/j.nurt.2009.08.002 · Cited by 305 · see citing works
“127 Cold and mechanical allodynia, but not thermal hyperalgesia, have been reported in a model of autoimmune encephalomyelitis in which mice were immunized with myelin oligodendrocyte glycoprotein (MOG(35-55))128; autoimmune encephalomyelitis has been postulated to underlie the development of neuropathic pain in MS.”
BackgroundDonvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.204 · Cited by 301 · see citing works
Deng, L., Guindon, J., Cornett, B., Makriyannis, A., Mackie, K., & Hohmann, A. G. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.009 · Cited by 200 · see citing works
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years
Maccarrone, M., Di Marzo, V., Gertsch, J., Grether, U., Howlett, A. C., Hua, T., Makriyannis, A., Piomelli, D., Ueda, N., & van der Stelt, M. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000600 · Cited by 183 · see citing works
Atwood, B. K., Wager‐Miller, J., Haskins, C. P., Straiker, A. J., & Mackie, K. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.074013 · Cited by 152 · see citing works
“††† p 0.001, versus untreated control. a Miller and Stella, 2008. b Ibrahim et al., 2003. c Thomas et al., 2005. d Khanolkar et al., 2007. e Yao et al., 2009. f Gallant et al., 1996.”
BackgroundInfluentialHsieh, G. C., Pai, M., Chandran, P., Hooker, B. A., Zhu, C. Z., Salyers, A. K., Wensink, E. J., Zhan, C., Carroll, W. A., Dart, M. J., et al. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01046.x · Cited by 139 · see citing works
“A-836339 is shown to exhibit relatively few off-target interactions (Yao et al., 2009), which is in contrast to the CB2-selective ligand AM1241 that exhibits significant radioligand binding affinity to a large number of additional GPCR and ion channel targets (Yao et al., 2008).”
BackgroundInfluentialSelf-citationTherapeutic Utility of Cannabinoid Receptor Type 2 (CB2) Selective Agonists
Han, S., Thatte, J., Buzard, D. J., & Jones, R. M. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4005626 · Cited by 134 · see citing works
Heteromerization of GPR 55 and cannabinoid CB 2receptors modulates signalling
Balenga, N. A. B., Martínez‐Pinilla, E., Kargl, J., Schröder, R. J., Peinhaupt, M., Platzer, W., Bálint, Z., Zamarbide, M., Dopeso‐Reyes, I. G., Ricobaraza, A., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12850 · Cited by 128 · see citing works
“As an example, one of the agonists used, A-836339, behaves as a potent selective CB2 receptor agonist (Yao et al., 2009) in HEK293 cells, but screening/functional assays require stable co-expression with a chimeric, Gαq/o5, protein (Yao et al., 2008).”
BackgroundBanister, S. D., & Connor, M. A. (2018) · Handbook of experimental pharmacology · doi:10.1007/164_2018_144 · Cited by 126 · see citing works
PET Imaging of Microglial Activation—Beyond Targeting TSPO
Janssen, B., Vugts, D. J., Windhorst, A. D., & Mach, R. H. (2018) · Molecules · doi:10.3390/molecules23030607 · Cited by 127 · see citing works
“7 nM, 425-fold selective over CB1 [14,15]) showed an increase in specific brain uptake in mice, 5 days after systemic injection of lipopolysaccharide (LPS), compared with control mice [14]; however, in a la er study with th same tracer, Pottier et al.”
ResultLötsch, J., Weyer-Menkhoff, I., & Tegeder, I. (2017) · European Journal of Pain · doi:10.1002/ejp.1148 · Cited by 118 · see citing works
“The evidence for a contribu- tion of CB2 for pain control mainly relies on studies with specific agonists (Yao et al., 2009; Gutierrez et al., 2011; Kinsey et al., 2011; Vincenzi et al., 2013), or maintenance of antinociceptive effects of CB1/CB2-agonists in CB1-deficient mice (Sain et al., 2009;…”
BackgroundTabrizi, M. A., Baraldi, P. G., Borea, P. A., & Varani, K. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00411 · Cited by 110 · see citing works
Horti, A. G., Gao, Y., Ravert, H. T., Finley, P. A., Valentine, H., Wong, D. F., Endres, C. J., Savonenko, A. V., & Dannals, R. F. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.05.058 · Cited by 108 · see citing works
Tiwari, V., Guan, Y., & Raja, S. N. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.05.002 · Cited by 103 · see citing works
Kinsey, S. G., Mahadevan, A., Zhao, B., Sun, H., Naidu, P. S., Razdan, R. K., Selley, D. E., Damaj, M. I., & Lichtman, A. H. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.09.004 · Cited by 94 · see citing works
“Of particular interest, unlike repeated morphine treatment, mice did not become tolerant to repeated administration of A-796260 or A-836339 (Yao et al., 2009;Yao et al., 2008).”
InfluentialSavonenko, A. V., Melnikova, T., Wang, Y., Ravert, H. T., Gao, Y., Koppel, J. L., Lee, D., Pletniková, O., Cho, E., Sayyida, N., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0129618 · Cited by 93 · see citing works
“Abbott Laboratories has recently synthetized a selective CB2 agonist, A836339, with very high CB2 binding affinity and excellent CB2/CB1 selectivity [20].”
BackgroundDiaz, P., Phatak, S. S., Xu, J. J., Fronczek, F. R., Astruc‐Diaz, F., Thompson, C. M., Cavasotto, C. N., & Naguib, M. (2009) · ChemMedChem · doi:10.1002/cmdc.200900226 · Cited by 88 · see citing works
Latest advances in cannabinoid receptor agonists
Thakur, G. A., Tichkule, R. B., Bajaj, S., & Makriyannis, A. (2009) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543770903436505 · Cited by 87 · see citing works
“In this regard, Abbott’s recent patent on co-administrating a CB2 selective agonist with CB1 antagonists appears to be an attractive and viable therapeutic approach.”
BackgroundInfluentialCannabinoids in pain management: CB1, CB2 and non-classic receptor ligands
Davis, M. P. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.918603 · Cited by 79 · see citing works
“The biologic significance of this is yet to be established; there may be a contribution of peripheral receptors to antinociception [184].”
BackgroundDynamic changes to the endocannabinoid system in models of chronic pain
Sagar, D. R., Burston, J. J., Woodhams, S. G., & Chapman, V. (2012) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0390 · Cited by 76 · see citing works
Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future
Whiting, Z. M., Yin, J., de la Harpe, S. M., Vernall, A. J., & Grimsey, N. L. (2022) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2022.06.010 · Cited by 70 · see citing works
Li, A.-L., Lin, X., Dhopeshwarkar, A., Thomaz, A. C., Carey, L. M., Liu, Y., Nikas, S. P., Makriyannis, A., Mackie, K., & Hohmann, A. G. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.113233 · Cited by 69 · see citing works
“Other putative CB2 agonists suggested to exhibit antiallodynic effects in CFA model are GW405833 (Li et al., 2017), AM1241 (Hsieh et al., 2011; Gao et al., 2016), A836339 (Yao et al., 2009; Hsieh et al., 2011), GW842166X (Giblin et al., 2007), and A-796260 (Yao et al., 2008); however, most studies have not thoroughly…”
BackgroundNovel thiazole derivatives: a patent review (2008 – 2012. Part 2)
Leoni, A., Locatelli, A., Morigi, R., & Rambaldi, M. (2014) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2014.910196 · Cited by 67 · see citing works
“Based on the results found in patents examined, it appears that Abbott improved upon the poor pharmacokinetic profile of known compounds, such as A-836339 [125] by using a prodrug approach as described in one of the applications [25].”
ResultChung, H., Choi, H., Heo, S., Kim, E., & Lee, J. (2013) · Forensic Toxicology · doi:10.1007/s11419-013-0213-6 · Cited by 62 · see citing works
Deng, L., Cornett, B., Mackie, K., & Hohmann, A. G. (2015) · Molecular Pharmacology · doi:10.1124/mol.115.098483 · Cited by 60 · see citing works
“Notably, no decrement in CB2-mediated antiallodynic effects was observed in CB1KOmice treated with daily administration of the high-dose CP55,940, similar to previous reports with CB2-preferring agonists (Yao et al., 2009; Deng et al., 2015).”
BackgroundResultBrownjohn, P. W., & Ashton, J. C. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.12.028 · Cited by 57 · see citing works
Wiley, J. L., Lefever, T. W., Marusich, J. A., Grabenauer, M., Moore, K. N., Huffman, J. W., & Thomas, B. F. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.07.016 · Cited by 58 · see citing works
Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor
Moldovan, R., Teodoro, R., Gao, Y., Deuther‐Conrad, W., Kranz, M., Wang, Y., Kuwabara, H., Nakano, M., Valentine, H., Fischer, S., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00554 · Cited by 58 · see citing works
Discovery of S-777469: An orally available CB2 agonist as an antipruritic agent
Odan, M., Ishizuka, N., Hiramatsu, Y., Inagaki, M., Hashizume, H., Fujii, Y., Mitsumori, S., Morioka, Y., Soga, M., Deguchi, M., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.02.072 · Cited by 56 · see citing works
CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain
Khasabova, I. A., Gielissen, J. M., Chandiramani, A., Harding-Rose, C., Odeh, D. A., Simone, D. A., & Seybold, V. S. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e3283474a6d · Cited by 53 · see citing works
“Evidence that systemic injection of naloxone blocks the inhibitory effect of systemic administration of AM1241 on thermal hyperalgesia in a rat model of peripheral inflammation (Yao et al., 2008) but not that of other synthetic CB2 receptor agonists under similar conditions (A-796260, Yao et al., 2008; A-836339, Yao e…”
InfluentialWilkerson, J. L., Gentry, K. R., Dengler, E. C., Wallace, J. A., Kerwin, A. A., Kuhn, M. N., Zvonok, A. M., Thakur, G. A., Makriyannis, A., & Milligan, E. D. (2012) · Brain and Behavior · doi:10.1002/brb3.44 · Cited by 51 · see citing works
“…chemotherapeutic agents (Rahn et al. 2007, 2010), and other pathological pain states (Nackley et al. 2004; Beltramo et al. 2006; Rahn et al. 2008; Yao et al. 2009), the current results extend these findings by showing that peri-spinal i.t. AM1241 injection acts to reverse CCIinduced allodynia.”
BackgroundResultCannabinoid receptors and pain
Starowicz, K., Małek, N., & Przewłocka, B. (2013) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.83 · Cited by 50 · see citing works
Malheiro, R. F., Carmo, H., Carvalho, F. D., & Silva, J. P. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106603 · Cited by 47 · see citing works
Janssen, B., & Mach, R. H. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.04.005 · Cited by 45 · see citing works
Winsauer, P. J., Molina, P. E., Amedee, A. M., Filipeanu, C. M., McGoey, R. R., Troxclair, D. A., Walker, E. M., Birke, L. L., Stouwe, C. V., Howard, J. M., et al. (2011) · Experimental and Clinical Psychopharmacology · doi:10.1037/a0023000 · Cited by 44 · see citing works
Endocannabinoid Receptor Pharmacology
Yao, B. B., & Mackie, K. (2009) · Current topics in behavioral neurosciences · doi:10.1007/978-3-540-88955-7_2 · Cited by 43 · see citing works
Self-citationParlar, A., Arslan, S. O., Doğan, M. F., Çam, S. A., Yal�in, A., Elibol, E., �zer, M., ��kardeş, F., & Kara, H. (2018) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2018.6753 · Cited by 43 · see citing works
“The high levels of CB2 express within the immune system including B cells, natural killer cells, monocytes, neutrophils, CD8 lymphocytes, CD4 lymphocytes (5,6).”
Mechanisms of cannabinoid tolerance
Piscura, M. K., Henderson, A. N., Barnes, R. C., Mitra, S., Guindon, J., & Morgan, D. J. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115665 · Cited by 38 · see citing works
Radioligands for positron emission tomography imaging of cannabinoid type 2 receptor
Spinelli, F., Mu, L., & Ametamey, S. M. (2017) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.3579 · Cited by 36 · see citing works
Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma
Zoerner, A. A., Stichtenoth, D. O., Engeli, S., Bátkai, S., Winkler, C., Schaumann, F., Janke, J., Holz, O., Krug, N., Tsikas, D., et al. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.94 · Cited by 35 · see citing works
Haruna, T., Soga, M., Morioka, Y., Hikita, I., Imura, K., Furue, Y., Yamamoto, M., Imura, C., Ikeda, M., Yamauchi, A., et al. (2015) · Pharmacology · doi:10.1159/000371890 · Cited by 34 · see citing works
Combination Chemistry: Structure–Activity Relationships of Novel Psychoactive Cannabinoids
Wiley, J. L., Marusich, J. A., & Thomas, B. F. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_17 · Cited by 33 · see citing works
Brogi, S., Corelli, F., Marzo, V. D., Ligresti, A., Mugnaini, C., Pasquini, S., & Tafi, A. (2010) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2010.11.034 · Cited by 33 · see citing works
McGaraughty, S., Chu, K. L., Dart, M. J., Yao, B. B., & Meyer, M. D. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2008.11.015 · Cited by 31 · see citing works
Self-citationLegal controls on cannabimimetics: An international dilemma?
King, L. A. (2013) · Drug Testing and Analysis · doi:10.1002/dta.1510 · Cited by 31 · see citing works
“It is believed to be more active at CB2 receptors, [36] but it could herald the start of a series of novel thiazole compounds.”
BackgroundLange, J. H. M., van der Neut, M. A. W., Wals, H. C., Kuil, G. D., Borst, A. J. M., Mulder, A. T., den Hartog, A. P., Zilaout, H., Goutier, W., van Stuivenberg, H. H., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.12.032 · Cited by 31 · see citing works
Inflammation in Experimental Models of α ‐Synucleinopathies
Harms, A. S., Kordower, J. H., Sette, A., Arlehamn, C. S. L., Sulzer, D. L., & Mach, R. H. (2020) · Movement Disorders · doi:10.1002/mds.28264 · Cited by 30 · see citing works
Cholesterol as a modulator of cannabinoid receptor CB2 signaling
Yeliseev, A., Iyer, M. R., Joseph, T. T., Coffey, N. J., Çınar, R., Zoubak, L., Kunos, G., & Gawrisch, K. (2021) · Scientific Reports · doi:10.1038/s41598-021-83245-6 · Cited by 28 · see citing works
The CB2 cannabinoid receptor as a therapeutic target in the central nervous system
Cabañero, D., Martín‐García, E., & Maldonado, R. J. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1971196 · Cited by 29 · see citing works
Caillé, F., Cacheux, F., Peyronneau, M., Jégo, B., Jaumain, E., Pottier, G., Ullmer, C., Grether, U., Winkeler, A., Dollé, F., et al. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b00746 · Cited by 27 · see citing works
Development of fluorinated CB2 receptor agonists for PET studies
Lueg, C., Schepmann, D., Günther, R., Brust, P., & Wünsch, B. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.09.040 · Cited by 26 · see citing works
Rahn, E. J., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2010) · The AAPS Journal · doi:10.1208/s12248-009-9170-8 · Cited by 24 · see citing works
“These latter effects are, therefore, almost certainly due to off-target binding (21).”
BackgroundCurto-Reyes, V., Boto, T., Hidalgo, A., Menéndez, L., & Baamonde, A. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.06.057 · Cited by 24 · see citing works
Translational NeuroImaging of the CNS: Novel Pathways to Drug Development
Fox, G. B., Chin, C.-L., Luo, F. R., Day, M., & Cox, B. F. (2009) · Molecular Interventions · doi:10.1124/mi.9.6.6 · Cited by 22 · see citing works
Self-citationBehavioral Neurobiology of the Endocannabinoid System
Kendall, D., & Alexander, S. (2009) · Current topics in behavioral neurosciences · doi:10.1007/978-3-540-88955-7 · Cited by 22 · see citing works
Novel strategies for the treatment of inflammatory hyperalgesia
Chopade, A. R., & Mulla, W. A. (2010) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-010-0784-7 · Cited by 21 · see citing works
“A-836339 [2,2,3,3-tetramethylcyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5dimethyl-3H-thiazol-(2Z)ylidene]-amide] + − [163]”
Basagni, F., Rosini, M., & Decker, M. W. (2020) · ChemMedChem · doi:10.1002/cmdc.202000298 · Cited by 21 · see citing works
Németh, A. G., Marlok, B., Domján, A., Gao, Q., Han, X., Keserű, G. M., & Ábrányi‐Balogh, P. (2021) · European Journal of Organic Chemistry · doi:10.1002/ejoc.202100548 · Cited by 20 · see citing works
Wilkerson, J. L., & Milligan, E. D. (2011) · ISRN Anesthesiology · doi:10.5402/2011/593894 · Cited by 20 · see citing works
“It was found in vitro that A-836339 could act as a CB1R agonist, and studies in vivo revealed that high doses of A-836339 produced CB1R-mediated psychotropic effects [183].”
Backgroundde Araújo, K. R. G., Fábris, A. L. D. S., Júnior, L. F. N., Ponce, J. D. C., Soares, A. L., Costa, J. L. R., & Yonamine, M. (2022) · Forensic Toxicology · doi:10.1007/s11419-022-00646-6 · Cited by 16 · see citing works
Sałaga, M., Zatorski, H., Zielińska, M., Mosińska, P., Timmermans, J., Kordek, R., Storr, M., & Fichna, J. (2017) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-017-1402-3 · Cited by 15 · see citing works
D’Elia, A., Schiavi, S., Soluri, A., Massari, R., Soluri, A., & Trezza, V. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.596509 · Cited by 14 · see citing works
Nan, J., Liu, J., Lin, G., Zhang, S., Xia, A., Zhou, P., Zhou, Y., Zhang, J., Zhao, J., Zhang, S., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01943 · Cited by 14 · see citing works
Cannabinoid CB2 receptor‐mediated analgesia: mechanism‐based insights and therapeutic potential
Guenther, K. G., & Hohmann, A. G. (2025) · British Journal of Pharmacology · doi:10.1111/bph.70116 · Cited by 12 · see citing works
“Many studies have shown the efficacy of CB 2 agonists in reducing mechanical and heat sensitivity in this model using rats (Grenald et al., 2017; Klawitter et al., 2024; LaBuda et al., 2005; Stachtari et al., 2016; Sun et al., 2014; Yao et al., 2008, 2009).”
Identification of a synthetic cannabinoid A-836339 as a novel compound found in a product
Uemura, N., Fukaya, H., Kanai, C., Yoshida, M., Nakajima, J., Takahashi, M., Suzuki, J., Moriyasu, T., & Nakae, D. (2013) · Forensic Toxicology · doi:10.1007/s11419-013-0201-x · Cited by 12 · see citing works
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [18F]LUZ5-d8
Ueberham, L., Gündel, D., Kellert, M., Deuther‐Conrad, W., Ludwig, F., Lönnecke, P., Kazimir, A., Kopka, K., Brust, P., Moldovan, R., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00195 · Cited by 11 · see citing works
Nelson, D. W., Frost, J. M., Tietje, K. R., Florjancic, A. S., Ryther, K. B., Carroll, W. A., Dart, M. J., Daza, A. V., Hooker, B. A., Grayson, G. K., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.01.121 · Cited by 11 · see citing works
Self-citationPET Imaging of Endocannabinoid System
Horti, A. G., Raymont, V., & Terry, G. E. (2014) · Springer eBooks · doi:10.1007/978-3-642-42014-6_11 · Cited by 11 · see citing works
First-in-human imaging using [11C]MDTC: a radiotracer targeting the cannabinoid receptor type 2
Du, Y., Coughlin, J. M., Brosnan, M. K., Chen, A. R., Shinehouse, L. K., Abdallah, R. H., Lodge, M. A., Mathews, W. B., Liu, C., Wu, Y., et al. (2023) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-023-06170-y · Cited by 10 · see citing works
“A-936339 was developed by Abbott Laboratories for studying CB2R activation in the central nervous system and for investigating pharmaceuticals targeting the CB2R [8].”
BackgroundAly, M. W., Ludwig, F., Deuther‐Conrad, W., Brust, P., Abadi, A., Moldovan, R., & Osman, N. A. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105191 · Cited by 9 · see citing works
Chapter 11 Recent Advances in the Discovery of CB2 Selective Agonists
Han, S., Thatte, J., & Jones, R. M. (2009) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(09)04411-x · Cited by 9 · see citing works
Hamzekalayi, M. R. A., Ardakani, M. H., Moeini, Z., Rezaei, R., Hamidi, N., Somee, L. R., Zolfaghar, M., Darzi, R., kamalipourazad, M., Riazi, G. H., et al. (2024) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2024.176679 · Cited by 7 · see citing works
Novel targets in pain research: The case for CB2 receptors as a biorational pain target
Brownjohn, P. W., & Ashton, J. C. (2009) · Current Anaesthesia and Critical Care · doi:10.1016/j.cacc.2009.07.014 · Cited by 7 · see citing works
Auvity, S., Attili, B. N. N. R., Caillé, F., Goislard, M., Cayla, J., Hinnen, F., Demphel, S., Brulon, V., Bottlaender, M., Leroy, C., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00348 · Cited by 5 · see citing works
PET Imaging of the Endocannabinoid System
Terry, G. E., Raymont, V., & Horti, A. G. (2020) · Springer eBooks · doi:10.1007/978-3-030-53176-8_12 · Cited by 5 · see citing works
MacNicol, E., Kokkinou, M., Navacerrada, M. E. S., Smith, D.-M., Li, J. S. Y., Simmons, C., Kim, E., Mesquita, M. S., Gonzalez, L. R., Andrews, T., et al. (2025) · Journal of Psychopharmacology · doi:10.1177/02698811251360745 · Cited by 4 · see citing works
“Similarly, animal studies have observed increases in cerebral blood volume, a metric related to CBF, following the administration of CB 1 R agonists (Chin et al., 2008; Yao et al., 2009).”
Glial Modulation in Pain States: Translation into Humans
Horvath, R. J., Romero-Sandoval, E. A., & Leo, J. A. D. (2010) · Europe PMC (PubMed Central) · Cited by 3 · see citing works
Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain
Rodriguez, C. E. B., Vanegas, S. O., Reck, A. M., Schrom, Y., & Kinsey, S. G. (2025) · Cannabis and Cannabinoid Research · doi:10.1089/can.2024.0088 · Cited by 2 · see citing works
Matthew, S., Ndong, C., Landry, R. P., Joyce, A., & Alfonso, E. (2012) · InTech eBooks · doi:10.5772/31686 · Cited by 2 · see citing works
“Similar findings have been described with another CB2 receptor agonist, A-836339 (Yao et al., 2009).”
BackgroundResultCannabinoid receptors as targets for drug discovery
Iliopoulos‐Tsoutsouvas, C., Iyer, M. R., & Makriyannis, A. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00052-2 · Cited by 1 · see citing works
Bannon, A. W. (2012) · Cambridge University Press eBooks · doi:10.1017/cbo9780511980053.010 · Cited by 1 · see citing works
Humanized CB1R and CB2R yeast biosensors enable facile screening of cannabinoid compoundsPreprint
Mulvihill, C. J., Lutgens, J., Gollihar, J., Bachanová, P., Marcotte, E. M., Ellington, A. D., & Gardner, E. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.12.511978 · Cited by 1 · see citing works
Applications of MRI to Psychopharmacology
Stein, D. J., Yang, Y., & Salmeron, B. J. (2011) · Springer eBooks · doi:10.1007/978-1-4419-0345-7_33
Leung, K. (2011) · National Center for Biotechnology Information (US) eBooks
Applications of MRI to Psychopharmacology
Stein, D. J., Yang, Y., & Salmeron, B. J. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1995-6_19
(2010) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0b013e3283372479
Applications of MRI to Psychopharmacology
Stein, D. J., Yang, Y., & Salmeron, B. J. (2023) · Springer eBooks · doi:10.1007/978-3-031-10909-6_37
Ueberham, L., Deuther‐Conrad, W., Lönnecke, P., Kazimir, A., & Hey‐Hawkins, E. (2025) · ChemMedChem · doi:10.1002/cmdc.202500251
Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery
Phatak, S. S. (2012) · Digital Commons-TMC (Texas Medical Center)
Bhattacharjee, P., Volesky, P. D., Shivshankar, S., Puhl, H. L., & Iyer, M. R. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052095
“It is selective for CB2, with Ki values of 0.64 nM for CB2 vs. 270 nM for the psychoactive CB1 receptor, exhibiting selective analgesic, anti-inflammatory and anti-hyperalgesic effects at low doses (Figure 5) [51,52].”
InfluentialBindingDB Entry 50005808: Development of fluorinated CB(2) receptor agonists for PET studies.
BindingDB (2020) · UC San Diego · doi:10.7270/q2q2435t
BindingDB (2013) · UC San Diego · doi:10.7270/q2db82vv
BindingDB (2015) · UC San Diego · doi:10.7270/q2b859m5
- Authors
- Yao, B. B., Hsieh, G., Daza, A. V., Fan, Y., Grayson, G. K., Garrison, T. R., El Kouhen, O., Hooker, B. A., Pai, M., Wensink, E. J., Salyers, A. K., Chandran, P., Zhu, C. Z., Zhong, C., Ryther, K., Gallagher, M. E., Chin, C.-L., Tovcimak, A. E., Hradil, V. P., Fox, G. B., Dart, M. J., Honore, P., & Meyer, M. D.
- Affiliations
- Abbott (United States) (US)
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 328
- Issue
- 1
- Pages
- 141-151
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2114691708
- Cited by
- 92
- References
- 41
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 7 · 2013: 6 · 2012: 7
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- antihyperalgesia, antiallodynia, inflammatory pain, neuropathic pain, complete Freund's adjuvant, chronic constriction injury, skin incision, locomotor activity
- MeSH terms
- Amides, Animals, Cell Line, Cricetulus, Cyclopropanes, Cricetinae, Hindlimb, Humans, Hyperalgesia, Inflammation, Kidney, Magnetic Resonance Imaging, Male, Pain, Postoperative Pain, Pain, Postoperative, Psychomotor Performance, CHO Cells, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Rats, Dermatologic Surgical Procedures
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review