The CB1 inverse agonist/antagonist SR141716A recently has been introduced for the management of obesity (rimonabant; Acomplia) and appears to have beneficial effects. However, its utility may be hampered in some individuals by adverse effects including nausea or emesis or by mood depression. The recent development of biochemically 'neutral' antagonists such as AM4113 (Sink et al. 2007) has allowed an initial evaluation of the proposition that the adverse effects of SR141716A are associated with its inverse agonist activity. Thus far, data comparing SR141716A and AM4113 across several species indicate that both drugs produce dose-related direct effects on operant behavior within the same range of doses that serve to antagonize the behavioral and hypothermic effects of a CB1 agonist. However, initial observations suggest that AM4113 may not produce preclinical indications of nausea or emesis. Further studies with AM4113 and other novel CB1 antagonists differing in efficacy should amplify our understanding of the relationship between the pharmacological activity of CB1 antagonists and their behavioral effects. KeywordsSR141716A; rimonabant; AM4113; AM4054; inverse agonism; neutral antagonism; behavior; hypothermia A rapid succession of events in the first half of the 1990s including the discovery of the cannabinoid-1 (CB1) receptor and the isolation and synthesis of its endogenous ligands anandamide and 2-AG, energized the explosion of scientific interest in cannabinoid pharmacology and the development of novel ligands, including those that produced Δ 9 THClike effects and those could counter, i.e., antagonize, the effects of Δ 9 THC and other CB1 agonists at the CB1 receptor. It is interesting that, notwithstanding the acknowledged medicinal value of cannabis products with CB1 agonist actions, the first major therapeutic agent to emerge from these research efforts has been the CB1 antagonist/inverse agonist SR141716A (rimonabant; [1]). Perhaps it is not surprising that its initial therapeutic targets have been based a The preparation of this manuscript and portions of the work described herein were supported under NIH/NIDA DA19205 b Portions of the work described herein have been presented previously at the 2005 meeting of the College on Problems of Drug Dependence in Orlando, FL and at the

Cannabinoid receptor 1 (CB 1 ) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB 1 neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB 1 inverse agonist SR141716A (rimonabant) and the CB 1 neutral antagonist AM4113 were compared for their ability to modify CB 1 receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB 1 full agonist AM4054. Results indicate that AM4054 serves as an effective CB 1 discriminative stimulus, with an onset and time course of action comparable with that of the CB 1 agonist D 9 -tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA 2 values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB 1 neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB 1 receptors.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

Taken together, these results demonstrate that serotonergic drugs can disrupt learning in monkeys, but indicate that MDMA-induced 5-HT neurotoxicity does not lead to disruptions in this particular type of serial learning task.