CP-809101

CP-809101 is a potent and selective 5-HT2C receptor agonist (pEC50 values are 9.96, 7.19 and 6.81 for human 5-HT2C, 5-HT2B and 5-HT2A receptors respectively). CP-809101 displays antipsychotic activity; suppresses condition avoidance responding (CAR) and inhibits PCP and amphetamine-stimulated hyperactivity in rats following subcutaneous administration.

Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101.[Pubmed:28338324]

ACS Chem Neurosci. 2017 May 17;8(5):1074-1084.

Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA2, and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

Lorcaserin and CP-809101 reduce motor impulsivity and reinstatement of food seeking behavior in male rats: Implications for understanding the anti-obesity property of 5-HT2C receptor agonists.[Pubmed:27241709]

Psychopharmacology (Berl). 2016 Jul;233(14):2841-56.

RATIONALE: The 5-HT2C receptor agonist lorcaserin (Belviq(R)) has been approved by the FDA for the treatment of obesity. Impulsivity is a contributory feature of some eating disorders. OBJECTIVE: Experiments investigated the effect of lorcaserin and the highly selective 5-HT2C agonist CP-809101 on measures of impulsivity and on reinstatement of food-seeking behaviour, a model of dietary relapse. The effect of both drugs on 22-h deprivation-induced feeding was also examined, as was the effect of prefeeding in each impulsivity test. RESULTS: Lorcaserin (0.3-0.6 mg/kg SC) and CP-809101 (0.6-1 mg/kg SC) reduced premature responding in rats trained on the 5-CSRTT and improved accuracy in a Go-NoGo task by reducing false alarms. At equivalent doses, both drugs also reduced reinstatement for food-seeking behaviour. Neither drug altered impulsive choice measured in a delay-discounting task. Lorcaserin (1-3 mg/kg SC) and CP-809101 (3-6 mg/kg SC) reduced deprivation-induced feeding but only at higher doses. CONCLUSIONS: These results suggest that in addition to previously reported effects on satiety and reward, altered impulse control may represent a contributory factor to the anti-obesity property of 5-HT2C receptor agonists. Lorcaserin may promote weight loss by improving adherence to dietary regimens in individuals otherwise prone to relapse and may be beneficial in cases where obesity is associated with eating disorders tied to impulsive traits, such as binge eating disorder.