Behavioral effects of the cannabinoid CB₁ receptor allosteric modulator ORG27569 in rats

Abstract

The cannabinoid CB1 receptor system is involved in feeding behaviors and the CB1 receptor antagonist SR141716A is an effective antiobesity drug. However, SR141716A also has serious side effects, which prompted the exploration of alternative strategies to modulate this important drug target. Recently a CB1 receptor allosteric modulating site has been discovered and the allosteric modulating activity of several modulators including ORG27569 has been characterized in vitro. Yet, little is known of the in vivo pharmacological effects of ORG27569. This study examined the behavioral pharmacology of ORG27569 in rats. ORG27569 (3.2–10 mg/kg, i.p.) selectively attenuated the hypothermic effects of CB1 receptor agonists CP55940 (0.1–1 mg/kg) and anandamide (3.2–32 mg/kg). In contrast, SR141716A only attenuated the hypothermic effects of CP55940 but not anandamide. SR141716A but not ORG27569 blocked CP55940-induced catalepsy and antinociception. In addition, ORG27569 did not modify SR141716A-elicited grooming and scratching behaviors. In feeding studies, ORG27569 decreased palatable and plain food intake which was partially blocked by CP55940. The hypophagic effect of ORG27569 developed tolerance after 4 days of daily 5.6 mg/kg treatment; however, the effect on body weight gain outlasted the drug treatment for 10 days. These data suggest that ORG27569 may not function as a CB1 receptor allosteric modulator in vivo, although its hypophagic activity still has potential therapeutic utility.

Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators

“…22 While we have seen similar negative results in catalepsy and antinociception in rats, Org27569 attenuated the hypothermic effects of CB1 receptor agonists CP55940 and anandamide. 23 Moreover, we also found that 1 resulted in a dose-related attenuation of both cue- and drug-induced reinstatement of cocaine- and methamphetamine-seeking behavior. 24 Finally, 1 showed high pharmacological selectivity against over forty GPCRs including those commonly involved in drug addictions.…”

A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

“…Moreover, this compound generally failed to modify the pharmacological effects of CB 1 orthosteric agonists in common rodent models indicative of CB 1 receptor activity (Gamage et al, 2014). Likewise, ORG27569 generally did not perform as a CB1 receptor allosteric modulator in rats (Ding et al, 2014). Although it attenuated both cue-and drug-induced reinstatement of cocaine and methamphetamine-seeking behavior in rats, CB 1 receptor involvement was not determined .…”

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

“…8 In animal behavioral studies, 1 had no effects on agonist-induced antinociception and catalepsy, grooming and scratching behaviors or drug discrimination. 15, 16 However, similar to CB1 antagonists/inverse agonists, 1 has been demonstrated to reduce food intake and to attenuate CP55,940-induced hypothermia in rats, albeit not in mice. 15, 16 Importantly, 1 also attenuated cue- and drug-induced reinstatement of extinguished cocaine- and methamphetamine-seeking behavior, 17 effects that have been previously observed with CB1 antagonists/inverse agonists, SR141716A and AM251 ( 46 ).…”

“…15, 16 However, similar to CB1 antagonists/inverse agonists, 1 has been demonstrated to reduce food intake and to attenuate CP55,940-induced hypothermia in rats, albeit not in mice. 15, 16 Importantly, 1 also attenuated cue- and drug-induced reinstatement of extinguished cocaine- and methamphetamine-seeking behavior, 17 effects that have been previously observed with CB1 antagonists/inverse agonists, SR141716A and AM251 ( 46 ). 18–21 On the other hand, reports on the in vivo effects of 2 have been confined to only one study, in which it decreased food intake and body weight.…”