VIP36 is a potent, selective and highly peripherally restricted Gi-biased agonist of cannabinoid receptor type 1 (CB1) with Ki of 22 nM in radioligand competition assays, exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance.
VIP36 displayed significantly reduced β-arrestin-2 recruitment (Emax=47%) compared with MDMB-FUBINACA (FCU, Emax=178%).
VIP36 showspotent peripheral CB1 receptor-dependent analgesia with limited analgesic tolerance.
VIP36 shows no detectable recruitment of β-arrestin-1 to CB1.
VIP36 produces analgesia that is dependent on peripheral CB1 receptors, is more than 2,400-fold more peripherally restricted over the parent template (FUB) and about 13-fold more restricted than CB13.
VIP36 shows limited tolerance and does not engage central CB1 receptors.
VIP36 produced analgesic actions in mouse models of inflammatory, neuropathic and migraine pain.