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
Samuel
D. Banister
Mitchell Longworth
Richard Kevin
Shivani Sachdev
Marina Santiago
Jordyn Stuart
James B. C. Mack
Michelle Glass
Iain S. McGregor
Mark Connor
Michael Kassiou
10.1021/acschemneuro.6b00137.s001
https://acs.figshare.com/articles/journal_contribution/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/3503201
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.
2016-07-15 00:00:00
5 F-ADB
5 F-AMB
THC
Cannabinoids 5 F-AMBICA
leucinate pendant group
SC
MDMB-FUBINACA
CB 1 activation
EC 50
CB receptor agonists
MDMB-CHMICA
mg
vivo
AMB-FUBINACA
CB 2
CB 1