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3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism.

Abstract

The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB₁ selectivity, with many lacking affinity for the CB₂ receptor. Affinity tended to be better when [³H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [³H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB₁ binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist-like effects in mice through a non-CB₁, non-CB₂ mechanism.

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  • Authors+Show Affiliations

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    RTI International, 3040 Cornwallis Road, Research Triangle Park, NC 27709-2194, USA. jwiley@rti.org

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    Source

    MeSH

    Animals
    Binding, Competitive
    Body Temperature
    Bornanes
    CHO Cells
    Cell Membrane
    Cricetinae
    Cyclohexanols
    Dronabinol
    Drug Inverse Agonism
    Female
    Freezing Reaction, Cataleptic
    Guanosine 5'-O-(3-Thiotriphosphate)
    Humans
    Male
    Mice
    Mice, Inbred C57BL
    Mice, Inbred ICR
    Mice, Knockout
    Motor Activity
    Pain Threshold
    Piperidines
    Pyrazoles
    Radioligand Assay
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Rimonabant
    Structure-Activity Relationship
    Transfection

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22085649

    Citation

    Wiley, Jenny L., et al. "3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB₁) Receptor Antagonist Rimonabant: Cannabinoid Agonist-like Effects in Mice Via non-CB₁, non-CB₂ Mechanism." The Journal of Pharmacology and Experimental Therapeutics, vol. 340, no. 2, 2012, pp. 433-44.
    Wiley JL, Selley DE, Wang P, et al. 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism. J Pharmacol Exp Ther. 2012;340(2):433-44.
    Wiley, J. L., Selley, D. E., Wang, P., Kottani, R., Gadthula, S., & Mahadeven, A. (2012). 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism. The Journal of Pharmacology and Experimental Therapeutics, 340(2), pp. 433-44. doi:10.1124/jpet.111.187815.
    Wiley JL, et al. 3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB₁) Receptor Antagonist Rimonabant: Cannabinoid Agonist-like Effects in Mice Via non-CB₁, non-CB₂ Mechanism. J Pharmacol Exp Ther. 2012;340(2):433-44. PubMed PMID: 22085649.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 3-Substituted pyrazole analogs of the cannabinoid type 1 (CB₁) receptor antagonist rimonabant: cannabinoid agonist-like effects in mice via non-CB₁, non-CB₂ mechanism. AU - Wiley,Jenny L, AU - Selley,Dana E, AU - Wang,Pinglang, AU - Kottani,Rudresha, AU - Gadthula,Srinivas, AU - Mahadeven,Anu, Y1 - 2011/11/15/ PY - 2011/11/17/entrez PY - 2011/11/17/pubmed PY - 2012/4/7/medline SP - 433 EP - 44 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 340 IS - 2 N2 - The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the 3-position may be involved in receptor recognition and agonist activity. The goal of the present study was to develop CB₁-selective compounds and explore further the SAR of 3-substitution on the rimonabant template. 3-Substituted analogs with benzyl and alkyl amino, dihydrooxazole, and oxazole moieties were synthesized and evaluated in vitro and in vivo. Several notable patterns emerged. First, most of the analogs exhibited CB₁ selectivity, with many lacking affinity for the CB₂ receptor. Affinity tended to be better when [³H]5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716), rather than [³H](-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP55,940), was used as the binding radioligand. Second, many of the analogs produced an agonist-like profile of effects in mice (i.e., suppression of activity, antinociception, hypothermia, and immobility); however, their potencies were not well correlated with their CB₁ binding affinities. Further assessment of selected analogs showed that none were effective antagonists of the effects of Δ⁹-tetrahydrocannabinol in mice, their agonist-like effects were not blocked by rimonabant, they were active in vivo in CB₁⁻/⁻ mice, and they failed to stimulate guanosine-5'-O-(3-[³⁵S]thio)-triphosphate binding. Several analogs were inverse agonists in the latter assay. Together, these results suggest that this series of 3-substituted pyrazole analogs represent a novel class of CB₁-selective cannabinoids that produce agonist-like effects in mice through a non-CB₁, non-CB₂ mechanism. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/22085649/3_Substituted_pyrazole_analogs_of_the_cannabinoid_type_1__CB₁__receptor_antagonist_rimonabant:_cannabinoid_agonist_like_effects_in_mice_via_non_CB₁_non_CB₂_mechanism_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=22085649 DB - PRIME DP - Unbound Medicine ER -