Pharmacological characterization of repeated administration of the first generation abused synthetic cannabinoid CP47,497

Abstract

A series of in vivo and in vitro assays were conducted to characterize the pharmacological effects of the first generation abused synthetic cannabinoid CP47,497, a racemic bicyclic cannabinoid that is similar in structure to the potent, high-efficacy synthetic cannabinoid CP55,940. CP47,497 was less efficacious than CP55,940 in activating G-proteins and dose-dependently produced common CB1 receptor-dependent pharmacological effects (i.e. catalepsy, hypothermia, antinociception, and hypolocomotion). CP47,497 also substituted for Δ9-tetrahydrocannabinol (THC) in the mouse drug discrimination, indicating that both drugs elicited a similar interceptive stimulus. The pharmacological effects of CP47,497 underwent tolerance following repeated administration and showed cross-tolerance following repeated THC administration, further suggesting a common cannabimimetic mechanism of action. Finally, the CB1 receptor antagonist rimonabant precipitated similar magnitudes of somatic withdrawal responses in mice treated repeatedly with THC or CP47,497. Taken together, these data verify the acute cannabimimetic effects of CP47,497, and indicate tolerance and dependence following repeated administration. The assays used here provide a straightforward approach to characterize the emerging next generation of abused synthetic cannabinoids.

The Cannabinoid Receptor Type 1 Positive Allosteric Modulator ZCZ011 Attenuates Naloxone-Precipitated Diarrhea and Weight Loss in Oxycodone-Dependent Mice

“…THC produces most of its pharmacological effects through the activation of two G-protein coupled receptors, cannabinoid receptor type 1 (CB 1 ; Matsuda et al, 1990) and type 2 (CB 2 ; Munro et al, 1993). THC and other CB 1 receptor agonists effectively attenuate withdrawal signs in opioid-dependent rodents (Hine, Friedman, et al, 1975;Bhargava, 1976a,b;Vela et al, 1995;Lichtman et al, 2001;Cichewicz and Welch, 2003;Ramesh et al, 2011;Gamage et al, 2015), though this pharmacological approach elicits acute cannabimimetic side effects and results in tolerance and physical dependence after repeated administration (Wiley and Martin, 2003;Grim et al, 2016;Trexler et al, 2018Trexler et al, , 2019. Alternatively, inhibitors of monoacylglycerol lipase (MAGL; Dinh et al, 2002) and fatty acid amide hydrolase (FAAH; Cravatt et al, 1996), which hydrolyze the respective endogenous cannabinoids, 2-arachidonoylglycerol (2-AG; Mechoulam et al, 1995;Sugiura et al, 1995) and anandamide (AEA; Devane et al, 1992), attenuate naloxone-precipitated and spontaneous withdrawal signs in morphine-dependent mice with reduced cannabimimetic side effects (Ramesh et al, 2011(Ramesh et al, , 2013Gamage et al, 2015;Wills et al, 2016).…”

Apparent CB1 Receptor Rimonabant Affinity Estimates: Combination with THC and Synthetic Cannabinoids in the Mouse In Vivo Triad Model

“…The primary contribution of the present study was the use of pA 2 /pK B analyses to determine CB 1 R heterogeneity of THC, the well characterized SCs CP55,940 and WIN55,212-2, the well characterized abused SCs JWH-073 and CP47,497, and the emerging novel abused SC A834,735D (Frost et al, 2008;Grim et al, 2016b;Marshell et al, 2014;Pertwee, 2006) in producing common in vivo cannabimimetic pharmacological effects (i.e., catalepsy, antinociception, and hypothermia) in male and female mice. These findings build on our recent study demonstrating that these drugs do not elicit relevant antinociceptive, cataleptic, and hypothermic effects in CB 1 (2/2) mice (Grim et al, 2016a).…”

Stratification of Cannabinoid 1 Receptor (CB1R) Agonist Efficacy: Manipulation of CB1R Density through Use of Transgenic Mice Reveals Congruence between In Vivo and In Vitro Assays

“…Studies used THC and the following five SCs reported to have higher efficacy than THC at CB 1 Rs (in order from purported highest to lowest efficacy): A-834,735 degradant (A-834,735D), WIN55,212-2 and CP55,940, JWH-073, and CP47,497 (Breivogel et al, 1998;Griffin et al, 1998;Auwärter et al, 2009;Atwood et al, 2011;Thomas and Wiley, 2014;Grim et al, 2016).The m opioid receptor agonist morphine and dopamine receptor antagonist chlorpromazine were tested as controls that were expected to produce in vivo effects independent of CB 1 R density. A-834,735D, WIN55,212-2, CP47,497, JWH-073, and chlorpromazine were obtained from Cayman Chemical (Ann Arbor, MI), and morphine, THC, and CP55,940 were generously supplied by the National Institute on Drug Abuse Drug Supply Program.…”

“…The drugs selected for study included THC, the well-characterized SCs CP55,940 and WIN55,212-2, two SCs associated with abuse CP47,497, JWH-073 (Atwood et al, 2011), and the heat degradant of the SC A-834,735 (Frost et al, 2010). Published (Griffin et al, 1998;Grim et al, 2016), and preliminary data suggest that these compounds display a range of CB 1 R efficacies as assessed in vitro by maximal stimulation of [ 35 S]GTPgS binding, such that low (e.g., THC), moderate (e.g., JWH-073, CP47,497), and high (e.g., CP55,940, WIN55,212-2, A-834,735D) degrees of CB 1 R efficacy are represented. The noncannabinoids morphine and chlorpromazine, which are active in subsets of these assays (Wiley and Martin, 2003), served as comparison drugs.…”