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

Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-<i>tert</i>-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 CB<sub>1</sub> (EC<sub>50</sub> = 0.45–36 nM) and CB<sub>2</sub> (EC<sub>50</sub> = 4.6–128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB<sub>1</sub> 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 CB<sub>1</sub>, but not CB<sub>2</sub>, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB<sub>1</sub>-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<sup>9</sup>-THC and earlier generations of SCs.