Elsevier

Neuropharmacology

Volume 52, Issue 2, February 2007, Pages 279-290
Neuropharmacology

CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity

https://doi.org/10.1016/j.neuropharm.2006.07.024Get rights and content

Abstract

CP-809,101 is a potent, functionally selective 5-HT2C agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT2C agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED50 = 4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT2C receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED50 values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT2C agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT2C agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.

Introduction

While antagonism at the dopamine D2 receptor remains a primary mechanism of antipsychotic drugs, the pharmacology of the newer atypical antipsychotics is not yet well understood. Although a number of 5-HT receptor subtypes have been implicated in the action of the atypical antipsychotics including 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7 (Meltzer and Nash, 1991), activity at 5-HT2 receptors has, in particular, been thought to play a significant role. To date, much work has focused on the 5-HT2A receptor subtype (for reviews see Schmidt et al., 1995, Meltzer et al., 2003). While the 5-HT2C receptor has received less attention, a number of recent studies have suggested a role for the 5-HT2C receptor both in terms of antipsychotic efficacy as well as side effects such as weight gain.

The 5-HT2C receptor subtype is widely distributed in both the rat and human brain with high expression found in cortical, striatal and limbic structures (Abramowski et al., 1995, Clemett et al., 2000), areas implicated in the pathophysiology of schizophrenia. Antagonism of the 5-HT2C receptor subtype is a common feature of several clinically used antipsychotics (Canton et al., 1994, Bymaster et al., 1999). Furthermore, several recent studies have suggested that 5-HT2C receptor inverse agonism may contribute to the actions of some antipsychotic drugs (Herrick-Davis et al., 2000, Rauser et al., 2001, Berg et al., 2005).

A number of studies examining the neurochemical effects of 5HT2C agonists suggest activation of this receptor may lead to decreases in dopamine in key brain regions thought to be associated with schizophrenia (for review, see Di Matteo et al., 2001). However, few behavioral studies have examined a role for 5HT2C agonists in animal models of psychosis and these studies have utilized the non-selective 5HT2C agonist, mCPP (Martin et al., 1988, Martin et al., 1989). Interestingly, several clinical studies have also assessed the effects of mCPP administration in schizophrenics (Abi-Saab et al., 2002, Iqbal et al., 1991, Kahn et al., 1992, Krystal et al., 1993), although the behavioral responses in patients in these studies have differed. Kahn et al. (1992) found a significant decrease in psychosis scores in schizophrenic patients, while other studies reported that mCPP significantly increased positive symptoms (Krystal et al., 1993, Iqbal et al., 1991). In light of the recent availability of more potent and selective 5HT2C agonists, it would be of interest to reassess the effects of these compounds in preclinical models of antipsychotic activity.

The role of 5-HT2C receptors in schizophrenia has also been investigated using genetic association studies. Although several early studies addressing 5-HT receptor polymorphisms in schizophrenic patients failed to identify any association with the disease (Sodhi et al., 1995, Wu et al., 1995), editing of 5-HT2C receptor RNA was reported to be reduced in the brains of schizophrenic patients (Sodhi et al., 2001). An initial report suggested a significant association between a variant 23ser allele and the response to clozapine, suggesting that this allele may be indicative of a positive response to antipsychotic treatment (Sodhi et al., 1995), subsequent studies have not replicated this work (Malhotra et al., 1996, Rietschel et al., 1997, Masellis et al., 1998).

In the present studies, we have examined the effects of a novel, selective 5-HT2C agonist, CP-809,101 (2-(3-chlorobenzyloxy)-6-(piperazin-1-yl)pyrazine, Fig. 1), in several animal models used to predict antipsychotic efficacy. The results demonstrate that the pharmacologic effects of CP-809,101, although mediated by agonist actions at 5-HT2C receptors, are very similar to those of the atypical antipsychotics. Furthermore, we have assessed the activity of CP-809,101 in animal models of antidepressant activity and cognition. The present studies demonstrated efficacy of CP-809,101 in the novel object recognition test, suggesting that 5-HT2C agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.

Section snippets

Membrane preparation

NIH 3T3 cells expressing the human form of either the 5-HT2C or the 5-HT2A receptor were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS, replaced with dialyzed serum the day before the assay). On the day of the assay, cells were harvested in dissociation buffer (Gibco, #13151-014), pelleted (1000 × g, 10 min at 4 °C) and re-suspended in homogenization buffer (10 mM HEPES, 1 mM EGTA, 1 mM EDTA, 10 mg/ml benzamidine (Sigma, #B6506), 10 mg/ml bacitracin (Sigma,

In vitro pharmacology

CP-809,101 is a potent, high affinity, 5-HT2C receptor full agonist that displays functional agonist selectivity (>500 fold using FLIPR comparisons) for the 5-HT2C receptor over other 5-HT2 receptor subtypes (data summarized in Table 1). As such, the compound displayed relatively low potency partial agonism at both the 5-HT2A and 5-HT2B receptors, however, there was less apparent binding selectivity across these three subtypes. To assess the binding specificity of CP-809,101, this compound was

Discussion

In vitro receptor binding and functional assays demonstrate that CP-809,101 is a potent and functionally selective 5-HT2C agonist. The present studies also suggest that CP-809,101 may be a novel potential atypical antipsychotic drug with a low risk of extrapyramidal symptoms. In our studies, CP-809,101, similar to other antipsychotic agents, was active in a dose-dependent manner in several animal models indicative of potential antipsychotic activity.

Our in vivo studies with CP-809,101 indicated

Acknowledgments

The authors would like to thank Dr John Kehne for helpful comments made during the preparation of this manuscript. Portions of this work were previously presented at the Society for Neuroscience Meeting, Washington, DC, November, 2005.

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