AM1710, a cannabilactone CB2 agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors. However, the signaling profile of AM1710 remains incompletely characterized. It is not known whether AM1710 behaves as a broad spectrum analgesic and/or suppresses the development of opioid tolerance and physical dependence. In vitro, AM1710 inhibited forskolin-stimulated cAMP production and produced enduring activation of ERK1/2 phosphorylation in HEK cells stably expressing mCB2. However, species differences in the signaling profile of AM1710 were observed between HEK cells stably expressing mCB2 and hCB2. In vivo, AM1710 produced a sustained inhibition of chemotherapy-induced allodynia induced by paclitaxel. Prior history of AM1710 treatment (5 mg/kg/day x 12 day, i.p.) delayed the development of analgesic tolerance to morphine and attenuated morphine-induced physical dependence in paclitaxel-treated mice. However, AM1710 (10 mg/kg, i.p.) did not precipitate CB1-receptor mediated withdrawal in mice rendered tolerant to Δ9-tetrahydrocannabinol, suggesting AM1710 does not behave as a functional CB1 antagonist in vivo. Furthermore, AM1710 (1, 3, 10 mg/kg, i.p.) did not suppress established mechanical allodynia induced by complete Freund9s adjuvant (CFA) or by partial sciatic nerve ligation (PSNL). Similarly, prophylactic and chronic dosing with AM1710 (10 mg/kg, i.p.) did not produce anti-allodynic efficacy in the CFA model. By contrast, gabapentin suppressed allodynia in both CFA and PSNL models. Our results indicate that AM1710 is not a broad spectrum analgesic agent in mice and suggest the need to identify signaling pathways underlying CB2 therapeutic efficacy to identify appropriate indications for clinical translation.

We recently reported on a controlled deactivation/detoxification approach for obtaining cannabinoids with improved druggability. Our design incorporates a metabolically labile ester group at strategic positions within the THC structure. We have now synthesized a series of (−)-Δ⁸-THC analogues encompassing a carboxyester group within the 3-alkyl chain in an effort to explore this novel cannabinergic chemotype for CB receptor binding affinity, in vitro and in vivo potency and efficacy, as well as controlled deactivation by plasma esterases. We have also probed the chain’s polar characteristics with regard to fast onset and short duration of action. Our lead molecule, namely 2-[(6aR,10aR)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-3-yl]-2-methyl-propanoic acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for CB receptors and is deactivated by plasma esterases while the respective acid metabolite is inactive. In further in vitro and in vivo experiments, the compound was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset of action.

Recognized as the gold-standard ideal fare, human milk has a unique composition that meets infants’ needs throughout development. Endocannabinoids and endocannabinoid-like compounds [endocannabinoid metabolome (ECM)] are endogenous lipid mediators derived from long-chain polyunsaturated fatty acids. Based on animal models, it has been proposed that endocannabinoid arachidonoyl glycerol (AG) plays a role in establishing the suckling response during lactation. In addition, endocannabinoid ethanolamides have been shown to stimulate food intake. The mechanisms of action and the role of the ECM in human milk are not fully understood. The present study aimed to characterize and quantify the ECM in human milk samples from an underserved population in Guatemala. Human milk samples were collected from lactating women (n = 26) for ECM characterization and quantification. Samples were taken at 3 different time points between 4 and 6 mo of lactation during maternal fasting. Human milk samples were analyzed by liquid chromatography-mass spectrometry. Identified members of the ECM were: arachidonoyl ethanolamide, palmitoyl ethanolamide (PEA), oleoyl ethanolamide, docosahexaenoyl ethanolamide, eicoapentaenoyl ethanolamide, eicosenoyl ethanolamide, AG, palmitoyl glycerol, oleoyl glycerol, docosahexaenoyl glycerol, eicosapentaenoyl glycerol, eicosenoyl glycerol, arachidonic acid (ARA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Overall, concentrations in the ethanolamide group were lower than the glycerols. A time effect was observed for ARA, DHA, EPA, and PEA across the 3 time points (P ≤ 0.05). Our study identified the ECM in mature human milk and provides the first report for a population with health disparities within a developing country. The few studies available have been conducted in developed countries. Hypotheses for future studies can be developed based on this study's data to help elucidate specific roles for members of the ECM and how this biological system modulates infant health and development.