AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Δ⁹-Tetrahydrocannabinol–Like Effects in Mice

Abstract

Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-, with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB 1 receptors, and in vivo for pharmacological effects in mice and in 9 -THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB 1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB 1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids.

Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in vivo assays in mice

“…In addition, efficacy differences may also contribute to the findings. Whereas THC has been reported to be a partial agonist at CB 1 receptors in some in vitro functional assays (Breivogel and Childers, 2000), albeit not in others (Laaris et al, 2010), synthetic cannabinoids (to the extent that they have been tested) are full agonists (Huffman et al, 2005; Wiley et al, 2015; Wiley et al, 2013). To determine whether cannabinoid receptor activation might have contributed to the variant effects of synthetic cannabinoids in the FOB (compared to THC), JWH-018 was tested in combination with a CB 1 receptor antagonist, rimonabant, and a CB 2 receptor antagonist, SR144528.…”

Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

“…As would be predicted by their high affinity for CB 1 receptors, AB-CHMINACA, AB-PINACA, and AB-FUBINACA fully substituted for Δ 9 -THC in rodents trained to discriminate Δ 9 -THC from vehicle [105,109], as did the quinolinyl carboxylates, PB-22 (1-pentyl-1H-indole-3-carboxylic acid 8-quinolinyl ester) and 5F-PB-22, and the amantane-derived indole AKB-48 [105]. In contrast, the benzimidazole FUBIMINA only partially substituted for Δ 9 -THC in mouse drug discrimination, which is consistent with its modest CB 1 receptor affinity [109].…”

“…Synthesis of selective CB 2 agonists and peripherally restricted CB 1 receptor agonists and antagonists are additional foci of drug development efforts [131,132], for which drug discrimination studies may predict whether lead candidates may possess unintended Δ 9 -THClike subjective effects. For cannabinoids synthesized for more nebulous purposes (e.g., "Spice," "herbal incense"), discrimination is a crucial tool in prediction of abuse liability and provision of scientific data required for classifying these compounds as schedule 1 [31, 105,109]. Use of selective CB 1 and CB 2 antagonists in the context of discrimination of cannabinoid agonists has confirmed CB 1 receptor mediation of the discriminative stimulus effects of Δ 9 -THC and psychoactive synthetic cannabinoids whereas rimonabant discrimination has been useful for examination of factors related to cannabinoid dependence.…”

Synthetic Pot: Not Your Grandfather’s Marijuana

“…In contrast, SCBs contained in seized K2/Spice products often exhibit sub-nanomolar CB 1 cannabinoid receptor affinity ( e.g, 5F-PB-22 [133], AK-B48 [133], AB-FUBINACA [134], ADB-FUBINACA, [134], JWH-122 [24], JWH-210 [21]). Newer SCBs derived from the indazole carboxamide scaffold, including AB-CHIMINACA [135] and AKB48 [23, 133], also have sub-nanomolar affinity for CB 1 cannabinoid receptors. In addition to such “ultra-high affinity” compounds, many other SCBs also bind with high affinity to CB 1 cannabinoid receptors, exhibiting Ki values between 1 and 20 nM ( e.g., JWH-018 [136], AB-PINACA [135], JWH-250, [137], STS-135 [133]).…”