作者: Desai, Rajeev I ; Makriyannis, Alexandros ; Ho, Thanh C ; AlKhelb, Dalal ; Georgiadis, Markos-Orestis ; Burke, Emily L ; Nikas, Spyros P ; Zvonok, Alexander ; Jiang, Shan ; Iliopoulos-Tsoutsouvas, Christos

The synthetic forms of delta-9-tetrahydrocannabinol (Δ⁹-THC), dronabinol or nabilone, have been approved to treat several indications. However, due to safety concerns their clinical utility remains limited. Consequently, there is a need for developing cannabinoid (CB) ligands that display better behavioral pharmacological profiles than Δ⁹-THC. Here, we utilized drug discrimination methods to compare the interoceptive effects of CB ligands that vary in potency, efficacy, and selectivity at the CB receptors, including two ligands, AM411 and AM4089, that show CB₁ partial agonist-like actions in vitro. Male rats were trained to discriminate 0.1 mg/kg AM2201 from saline under a fixed-ratio (FR) 10 response schedule of food reinforcement. After establishing AM2201's discriminative-stimulus effects, pretreatment tests with the CB₁ antagonist/inverse agonist rimonabant blocked AM2201's effects, whereas the peripherally-restricted antagonist AM6545 had no effect. Next, the generalization profiles of AM411 and AM4089 with CB₁ full agonists (JWH-018, CP-55,940, AM8936), partial agonist (Δ⁹-THC), and non-cannabinoids (fentanyl, atropine) were compared. The CBs either fully (AM2201, CP-55,940, JWH-018, AM8936, Δ⁹-THC) or partially (AM411, AM4089) substituted for AM2201, whereas fentanyl and atropine did not produce AM2201-like effects. All CB drugs were more potent than Δ⁹-THC and correlation analysis confirmed that the relative behavioral potencies of CBs corresponded strongly with their relative affinities at the CB₁ but not CB₂ receptors. Together, our results further demonstrate that AM411 and AM4089 exhibit better pharmacological profiles compared to Δ⁹-THC, in that they are more potent and display in vivo partial agonist-like actions that are centrally mediated via CB₁ receptors.

2022-05-01·FASEB JOURNAL

Effects of Cannabinoid Agonists and Antagonists in Rats Discriminating Fentanyl

Article

作者: Iliopoulos‐Tsoutsouvas, Christos ; Nikas, Spyridon P. ; Papanastasiou, Ioannis ; Makriyannis, Alexandros ; Jiang, Shan ; Zvonok, Alexander ; Kirunda, Andre ; Alkhelb, Dalal A. ; Vemuri, Kiran ; Desai, Rajeev I.

Extensive evidence suggests the existence of a functional interaction between endogenous cannabinoids and opioid systems. Targeting cannabinoid CB1 receptors might be a promising approach for developing new medications for opioid addiction. The present studies were undertaken to evaluate the effects of CB1 agonists and antagonists in rats (n=8) trained to discriminate, i.p., injections of 0.032 mg/kg fentanyl from saline on a 10‐response fixed‐ratio (FR‐10) schedule of food reinforcement. Results show that the µ‐opioid agonists (fentanyl, morphine, and oxycodone) substituted fully for fentanyl, whereas the muscarinic antagonist atropine did not substitute for fentanyl. The CB1 agonists Δ9‐THC, AM2201, and AM8936 all partially substituted for fentanyl’s discriminative‐stimulus effects suggesting some overlap in the discriminative‐stimulus effects of cannabinoid agonists and fentanyl. Pretreatment studies with a µ‐opioid receptor antagonist show that naltrexone antagonized fentanyl’s effects. Interestingly, pretreatment studies with CB1 antagonists show that rimonabant (inverse agonist) produced some attenuation of fentanyl’s discriminative‐stimulus effects at doses that significantly decreased response rates, whereas the neutral CB1 antagonist AM4113 blocked fentanyl discrimination at doses that did not modify rates of responding. Our findings are consistent with our recent work showing that AM4113 attenuates heroin self‐administration in rats, without producing depressive‐like effects. Collectively, these data suggests that CB1 neutral antagonists that block CB1 receptors with rimonabant‐like potency, devoid of unwanted side‐effects, may be therapeutically advantageous for countering the abuse‐related behavioral effects of opioids.

2022-02-01·European journal of medicinal chemistry1区 · 医学

Improved cyclobutyl nabilone analogs as potent CB1 receptor agonists

1区 · 医学

Article

作者: Ji, Lipin ; Zvonok, Nikolai ; Bohn, Laura M ; Brust, Christina A ; Tran, Ngan K ; Paronis, Carol A ; Papanastasiou, Ioannis P ; Iliopoulos-Tsoutsouvas, Christos ; Makriyannis, Alexandros ; Nikas, Spyros P ; Ma, Xiaoyu ; Tong, Fei ; Georgiadis, Markos-Orestis ; Wood, JodiAnne T

In earlier work, we explored the SAR for the C3 side chain pharmacophore in the hexahydrocannabinol template represented by the drug nabilone, which resulted in the development of AM2389. In an effort for further optimization, we have merged features of nabilone and AM2389 and explored the C3 side chain with varying chain lengths and terminal substitutions. Of the compounds described here, a nabilone analog, AM8936, with the C6'-cyano-substituted side chain, was identified as the most successful analog capable of serving as a potential candidate for further development and a valuable tool for further in vivo studies. AM8936 behaved as a balanced and potent CB1 agonist in functional assays and was a potent and efficacious CB1 agonist in vivo. Our SAR studies are highlighted with the docking of AM8936 on the crystal structure of the hCB1 receptor.

100 项与 AM-8936 相关的药物交易

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