Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues

Abstract

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45-36 nM) and CB2 (EC50 = 4.6-128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1-1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB1, but not CB2, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ(9)-THC and earlier generations of SCs.

A new designer drug 5F-ADB activates midbrain dopaminergic neurons but not serotonergic neurons

“…2D, E), suggesting that the activating effect of 5F-ADB on dopaminergic neurons was mainly produced by activation of local CB 1 receptors. Furthermore, according to a previous in vitro assay, 5F-ADB displayed agonist activity at both CB 1 and CB 2 receptors (Banister et al, 2016). Considering that CB 2 receptors are expressed on dopaminergic neurons and decrease dopaminergic-neuron activity (Zhang et al, 2014), our results suggest the possibility that 5F-ADB has dual effects on dopaminergic neurons -i.e., potent activation via CB 1 receptors and moderate inactivation via CB 2 receptors.…”

“…Considering that CB 2 receptors are expressed on dopaminergic neurons and decrease dopaminergic-neuron activity (Zhang et al, 2014), our results suggest the possibility that 5F-ADB has dual effects on dopaminergic neurons -i.e., potent activation via CB 1 receptors and moderate inactivation via CB 2 receptors. Additionally, this idea is supported by the fact that ADB-induced increases in dopaminergic firing activity were relatively weak compared to the expected response from in vitro CB 1 affinity for 5F-ADB (Banister et al, 2016).…”

“…Recently, new synthetic cannabinoids called "designer drugs" are being used widely and cause significant problems (Castellanos and Gralnik, 2016). Among these cannabinoids, N-[[1-(5-fluoropentyl)-1H-indazol-3-yl]carbonyl]-3-methyl-D-valine methyl ester (5F-ADB) shows potent activity on cannabinoid 1 (CB 1 ) receptors, resulting in high toxicity (Banister et al, 2016). 5F-ADB was first identified in human specimens in 2014, and a postmortem study showed that a sufficient concentration of 5F-ADB enters the brain after inhalation, suggesting that 5F-ADB affects brain endocannabinoid systems (Hasegawa et al, 2015).…”

Identification of New Synthetic Cannabinoid ADB-CHMINACA (MAB-CHMINACA) Metabolites in Human Hepatocytes

“…1). Binding affinity for CB 1 receptors and half maximal effective concentration were K i = 0.289 nM and EC 50 = 0.620 nM, respectively (no data for CB 2 ) (11), making ADB-CHMINACA one of the most potent SC to date (1)(2)(3)(4). Its binding affinity and potency are 140 and 270 times higher than those of THC, respectively (1,3).…”

“…SC potency and binding affinity for CB 1 and CB 2 are often much higher than classic cannabinoids, such as Δ 9 -tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis (1)(2)(3)(4). Consequently, SC are actively abused since 2008 as Blegal highs^ (5).…”