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Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects.

Abstract

Cannabinoid CB(2) agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB(2) agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB(1) (SR141716) and CB(2) (SR144528) antagonists. AM1710 (0.1-10mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB(2) agonist (R,S)-AM1241 (1mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1mg/kg i.p.) dose of AM1710 was blocked selectively by the CB(2) antagonist SR144528 (6mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5mg/kg i.p.) was blocked by either SR144528 (6mg/kg i.p.) or SR141716 (6mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB(2)-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB(1)-mediated antinociceptive effects of this compound may be attributable to peripheral CB(1) activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.

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    ,

    Program in Neuroscience, Biomedical and Health Sciences Institute, University of Georgia, Athens, GA, United States. rahn.eli@uky.edu

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    MeSH

    Analgesics
    Animals
    Behavior, Animal
    Binding, Competitive
    Blood-Brain Barrier
    Bornanes
    Cannabinoids
    Central Nervous System
    Chromones
    HEK293 Cells
    Humans
    Male
    Mice
    Pain Threshold
    Piperidines
    Pyrazoles
    Rats
    Rats, Sprague-Dawley
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Recombinant Proteins
    Rimonabant

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21382397

    Citation

    Rahn, Elizabeth J., et al. "Pharmacological Characterization of AM1710, a Putative Cannabinoid CB2 Agonist From the Cannabilactone Class: Antinociception Without Central Nervous System Side-effects." Pharmacology, Biochemistry, and Behavior, vol. 98, no. 4, 2011, pp. 493-502.
    Rahn EJ, Thakur GA, Wood JA, et al. Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects. Pharmacol Biochem Behav. 2011;98(4):493-502.
    Rahn, E. J., Thakur, G. A., Wood, J. A., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2011). Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects. Pharmacology, Biochemistry, and Behavior, 98(4), pp. 493-502. doi:10.1016/j.pbb.2011.02.024.
    Rahn EJ, et al. Pharmacological Characterization of AM1710, a Putative Cannabinoid CB2 Agonist From the Cannabilactone Class: Antinociception Without Central Nervous System Side-effects. Pharmacol Biochem Behav. 2011;98(4):493-502. PubMed PMID: 21382397.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Pharmacological characterization of AM1710, a putative cannabinoid CB2 agonist from the cannabilactone class: antinociception without central nervous system side-effects. AU - Rahn,Elizabeth J, AU - Thakur,Ganesh A, AU - Wood,Jodi Anne T, AU - Zvonok,Alexander M, AU - Makriyannis,Alexandros, AU - Hohmann,Andrea G, Y1 - 2011/03/05/ PY - 2010/11/29/received PY - 2011/02/21/revised PY - 2011/02/24/accepted PY - 2011/3/9/entrez PY - 2011/3/9/pubmed PY - 2011/8/25/medline SP - 493 EP - 502 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol. Biochem. Behav. VL - 98 IS - 4 N2 - Cannabinoid CB(2) agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB(2) agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB(1) (SR141716) and CB(2) (SR144528) antagonists. AM1710 (0.1-10mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB(2) agonist (R,S)-AM1241 (1mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1mg/kg i.p.) dose of AM1710 was blocked selectively by the CB(2) antagonist SR144528 (6mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5mg/kg i.p.) was blocked by either SR144528 (6mg/kg i.p.) or SR141716 (6mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB(2)-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB(1)-mediated antinociceptive effects of this compound may be attributable to peripheral CB(1) activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/21382397/abstract/Pharmacological_characterization_of_AM1710_a_putative_cannabinoid_CB_2__agonist_from_the_cannabilactone_class:_Antinociception_without_central_nervous_system_side_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(11)00070-0 DB - PRIME DP - Unbound Medicine ER -