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Chromenopyrazoles: non-psychoactive and selective CB? cannabinoid agonists with peripheral antinociceptive properties.

ABSTRACT: The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB?-mediated side effects are due to the fact that CB? receptors are largely expressed in the central nervous system (CNS). As it is known that CB? receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB? and CB? receptors. Structural features required for CB?/CB? affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB? ligands. These modeling studies suggest that full CB? selectivity over CB? can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In?vivo behavioral tests were then carried out on the most effective CB? cannabinoid agonist, 13?a. Chromenopyrazole 13?a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood-brain barrier. Moreover, 13?a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot-plate test, the antinociception induced by 13?a in the orofacial test could be mediated through peripheral mechanisms.

SUBMITTER: Cumella J

PROVIDER: S-EPMC4049093 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Chromenopyrazoles: non-psychoactive and selective CB₁ cannabinoid agonists with peripheral antinociceptive properties.

Cumella Jose J Hernández-Folgado Laura L Girón Rocio R Sánchez Eva E Morales Paula P Hurst Dow P DP Gómez-Cañas Maria M Gómez-Ruiz Maria M Pinto Diana C G A DC Goya Pilar P Reggio Patricia H PH Martin María Isabel MI Fernández-Ruiz Javier J Silva Artur M S AM Jagerovic Nadine N

ChemMedChem 20120202 3

The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB₁-mediated side effects are due to the fact that CB₁ receptors are largely expressed in the central nervous system (CNS). As it is known that CB₁ receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesi ...[more]

PMID: 22302767

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Project description:Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and IL-17 secretion. However, the mechanisms of CBD anti-inflammatory activities are unclear.Here we analyzed the effects of CBD on splenocytes (source of accessory T cells and antigen presenting cells (APC)) co-cultured with MOG35-55-specific T cells (TMOG) and stimulated with MOG35-55. Using flow cytometry, we evaluated the expression of surface activation markers and inhibitory molecules on T cells and B cells. TMOG cells were purified using CD4 positive microbead selection and submitted for quantitative PCR and microarray of mRNA transcript analyzes. Cell signaling studies in purified TMOG were carried out using immunoblotting.We found that CBD leads to upregulation of CD69 and lymphocyte-activation gene 3 (LAG3) regulatory molecules on CD4(+)CD25(-) accessory T cells. This subtype of CD4(+)CD25(-)CD69(+)LAG3(+) T cells has been recognized as induced regulatory phenotype promoting anergy in activated T cells. Indeed, we observed that CBD treatment results in upregulation of EGR2 (a key T cell anergy inducer) mRNA transcription in stimulated TMOG cells. This was accompanied by elevated levels of anergy promoting genes such as IL-10 (anti-inflammatory cytokine), STAT5 (regulatory factor), and LAG3 mRNAs, as well as of several enhancers of cell cycle arrest (such as Nfatc1, Casp4, Cdkn1a, and Icos). Moreover, CBD exposure leads to a decrease in STAT3 and to an increase in STAT5 phosphorylation in TMOG cells, positive and negative regulators of Th17 activity, respectively. In parallel, we observed decreased levels of major histocompatibility complex class II (MHCII), CD25, and CD69 on CD19(+) B cells following CBD treatment, showing diminished antigen presenting capabilities of B cells and reduction in their pro-inflammatory functions.Our data suggests that CBD exerts its immunoregulatory effects via induction of CD4(+)CD25(-)CD69(+)LAG3(+) cells in MOG35-55-activated APC/TMOG co-cultures. This is accompanied by EGR2-dependent anergy of stimulated TMOG cells as well as a switch in their intracellular STAT3/STAT5 activation balance leading to the previously observed decrease in Th17 activity.

Dataset Information

Chromenopyrazoles: non-psychoactive and selective CB? cannabinoid agonists with peripheral antinociceptive properties.

Publications

Chromenopyrazoles: non-psychoactive and selective CB₁ cannabinoid agonists with peripheral antinociceptive properties.

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