Discriminative stimulus properties of 3-substituent rimonabant analogs

Abstract

Cannabinoid agonists (e.g., THC) dose-dependently decrease locomotor activity and body temperature and produce antinociception and catalepsy. Drugs that produce this tetrad of effects within a limited dose range are likely to function as CB1 receptor agonists. A structure activity relationship study from our laboratory investigating analogs of the CB1 antagonist rimonabant revealed that certain alterations in the 3-substituent of rimonabant’s pyrazole core conferred agonist-like properties in the tetrad. Interestingly, these effects were present in CB1 -/- mice, and were not reversed by rimonabant in wild-type mice. The present study evaluated two novel 3-substituent rimonabant analogs, O-6629 and O-6658 in the tetrad and drug discrimination, a preclinical model of drug subjective effects that possesses a high degree of pharmacological specificity. Drugs that elicit cannabinergic psychoactive effects in humans are likely to produce THC-like operant responding in animals trained to discriminate between the interoceptive stimuli produced by THC relative to vehicle. O-6629 and O-6658 decreased locomotor activity and body temperature and produced catalepsy. O-6629, but not O-6658 produced significant antinociception. However, these drugs differed from THC in regard to the magnitude of tetrad effects observed. These analogs also failed to elicit THC-like discriminative stimulus effects, nor did they antagonize THC’s discriminative stimulus in mice discriminating 5.6 mg/kg THC from vehicle. Finally, mice were trained to discriminate 5.6 mg/kg O-6629 from vehicle. O-6658 produced full substitution for O-6629, whereas the cannabinoid agonists THC and anandamide did not. O-6629’s discriminative stimulus failed to generalize to rimonabant, cocaine or morphine, whereas WIN 55,212-2 and nicotine evoked partial substitution. These results suggest that these analogs might exert their pharmacological properties through a novel cannabinoid receptor, as has been proposed for WIN 55,212-2 and anandamide. Additionally, O-6629’s discriminative stimulus may involve nicotinic acetylcholine or dopaminergic components. Future directions include determining whether the partial substitution observed with nicotine was mediated through a nicotinic mechanism. Tests with chlorpromazine, an antipsychotic that is a false positive in the tetrad, and diazepam, which produces partial substitution for THC’s discriminative stimulus through a GABAergic mechanism are also planned.