Structure-activity relationships for 5F-MDMB-PICA and its 5F-pentylindole analogs to induce cannabinoid-like effects in mice

Defining Steric Requirements at CB1 and CB2 Cannabinoid Receptors Using Synthetic Cannabinoid Receptor Agonists 5F-AB-PINACA, 5F-ADB-PINACA, PX-1, PX-2, NNL-1, and Their Analogues

“…Although we did not systematically measure other tetrad behaviors, no other behavioral responses (e.g., catalepsy) were noted by the experimenters, and this hypothermia model is highly sensitive to the CB 1 activation produced by other SCRAs. ,,,,,, These data show that in vivo, 15 (PX-1) and 19 (PX-2) are less efficacious hypothermic agents than THC, which reduces mouse core body temperature by approximately 4 °C at 30 mg/kg (i.p) . Because THC is a potent and moderately efficacious agonist at CB 1 receptors, it therefore appears that 15 (PX-1) and 19 (PX-2) are, at best, CB 1 agonists of low-to-moderate potency and efficacy, unlike the majority of recent SCRAs on the NPS market, nearly all of which are potent and efficacious CB 1 agonists in vitro, and potent cannabimimetic agents in vivo. ,,,, …”

“…In contrast to the compounds mentioned above, benzylic SCRAs such as SDB-006 ( 36 ) and 5F-SDB-006 ( 37 ) showed moderate CB 1 potency in vitro, , but negligible cannabimimetic potency in rodents, , possibly due to differences in physicochemical properties or metabolism. Taken together, these studies indicate that not all the putative SCRAs identified in NPS markets, nor SCRAs with confirmed in vitro potency, are potent and centrally cannabimimetic in vivo.…”

“…For selected SCRAs, confirmed interactions with noncannabinoid targets include various 5-HT receptors (1A, 2B, 2C, and 6), 37,83 GPR18 and GPR55, 20,24 M1, 37 GABA-A, 37 hERG channels, 37 and T-type calcium channels. 84 In contrast to the compounds mentioned above, benzylic SCRAs such as SDB-006 (36) and 5F-SDB-006 (37) showed moderate CB 1 potency in vitro, 15,85 but negligible cannabimimetic potency in rodents, 42,85 possibly due to differences in physicochemical properties or metabolism. Taken together, these studies indicate that not all the putative SCRAs identified in NPS markets, nor SCRAs with confirmed in vitro potency, are potent and centrally cannabimimetic in vivo.…”

“…80 Because THC is a potent and moderately efficacious agonist at CB 1 receptors, it therefore appears that 15 (PX-1) and 19 (PX-2) are, at best, CB 1 agonists of low-to-moderate potency and efficacy, unlike the majority of recent SCRAs on the NPS market, nearly all of which are potent and efficacious CB 1 agonists in vitro, and potent cannabimimetic agents in vivo. 28,30,41,42,69 Curiously, several other SCRAs detected in drug markets have also shown negligible cannabimimetic activity in vivo, suggesting that these substances are released onto the NPS market without any pharmacological evaluation. For example, adamantane-derived indoles AB-001 (30, Figure 7) and AB-002 (31) were poor CB 1 agonists in vitro and showed only hypothermic trends in rats at doses up to 30 mg/kg.…”

“…Since the detection of the first examples of SCRAs in commercial products in 2008, this class has undergone increasing structural diversification. − The earliest SCRAs were 3-acylindole derivatives such as JWH-018 ( 1 , Figure ) and XLR-11 ( 2 ), with structure evolution to indole-3-carboxylates (e.g., BB-22, 3 ), indazole-3-carboxamides (e.g., AKB48, 4 ), and 7-azaindole-3-carboxamides (e.g., CUMYL-5F-P7AICA, 5 ) . The basic in vitro structure–affinity and structure–activity relationships (SARs) at CB 1 and CB 2 receptors for various historical classes of SCRAs have been described, with most examples demonstrating nanomolar affinity and potency at both receptor subtypes. − The evaluation of selected SCRAs in rodents has revealed that they generally possess typical cannabimimetic profiles in vivo, inducing hypothermia, bradycardia, catalepsy, hypolocomotion, and antinocicpetion. − ,,− …”