Therapeutic Potential of 5HT2C Receptor Drugs for Reward Related Behavioral Problems

Pharmaceutical research into the identification of subtype selective 5-HT2C agonists has been an ongoing effort since the mid-1990s, driven largely by the potential of such drugs to treat obesity (Nilsson 2006). This has not been an immediately successful enterprise, largely because of the high sequence homology between the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes (Hoyer et al. 2002; Barnes and Sharp 1999) and the negative impact of direct 5-HT2A and 5-HT2B receptor activation. The hallucinogenic properties of the indoleamine and phenylalkylamine drug classes are believed to be attributable to 5-HT2A receptor agonism (Geyer and Vollenweider 2008) and the cardiac valvulopathies associated with the antiparkinsonian drug pergolide (Antonini and Poewe 2007), and the 5-HT releaser dex fenfluramine are likely 5-HT2B receptor mediated (Fitzgerald et al. 2000; Rothman et al. 2000). Therefore, from a safety perspective alone, 5-HT2C receptor agonists with a high degree of subtype selectivity are necessary.

A number of subtype selective 5-HT2C agonists have now appeared in the patent literature (Nilsson 2006). The most advanced of these, lorcaserin (formerly ADP356), has recently completed a phase III trial for obesity. As the first selective 5-HT2C agonist to undergo extensive clinical evaluation, lorcaserin could serve as a useful guide when considering the therapeutic potential of this drug class. Lorcaserin was discovered by Arena Pharmaceuticals (Smith et al. 2008) and based on in vitro screening across clonal cell lines expressing h5-HT2 receptors it has approximately 15- and 100-fold selectivity for h5-HT2C against h5-HT2A and h5-HT2B receptors (Thomsen et al. 2008). In animal models of obesity, lorcaserin reduces body weight gain (Thomsen et al. 2008). The inhibitory effects of this drug on feeding and motor behavior are absent in 5-HT2C receptor knockout mice (Fletcher et al. 2009) confirming a 5-HT2C receptor-mediated action. In a randomized, double-blind, parallel arm phase II study in 469 men and women with BMI 30-45 kg/m2, lorcaserin (10 mg q.d., 15 mg q.d., 10 mg b.i.d.) was well tolerated over a 12-week treatment period, with dose-related and progressive weight loss compared with placebo (Smith et al. 2009). The magnitude of this change relative to placebo reached 3.6 kg at the 10 mg b.i.d dose, which is comparable to weight reductions produced by sibutramine and rimonabant over equivalent or longer-term trials (see Smith et al. 2009). Importantly, regular echocardiography measurement failed to identify any treatment-related effects on cardiac function, and no adverse effects on cognition, perception, or mood were reported. Most recently, these promising results in terms of efficacy, tolerability, and cardiac safety, have been extended in a phase III placebo controlled trial involving over 3,000 subjects (Arena press release, March 30, 2009, =373684). Taken together, these data suggest that as a drug class 5-HT2C receptor agonists have a therapeutic potential for the treatment of obesity, and providing that suitable selectivity for the 5-HT2C receptor is met, such drugs at least on current evidence, appear to be well tolerated following sustained dosing.

Because 5-HT2C receptors modulate reward-related behaviors, a logical question about the therapeutic potential of drugs like lorcaserin is whether this can be extended to the treatment of drug abuse. Several neurochemical systems, including DA, endogenous opioids, and cannabinoids, that are involved in drug abuse and dependence are also involved in the control of different aspects of feeding behavior (Kirkham 2009; Barbano and Cador 2007; Barbano et al. 2009). Similarly, the neuropeptides leptin and orexin that are involved in mediating aspects of feeding behavior also modulate reward-related behaviors (Borgland et al. 2006; Fulton et al. 2000). Thus, there is convergence and overlap of brain mechanisms and systems involved in reward-related behaviors relevant to obesity and substance abuse (Trinko et al. 2007; Volkow and Wise 2005). It is feasible then that a serotonergic drug that is effective in treating obesity may have potential in treating addiction.

There are some reports of serotonergic drugs that may affect weight gain in obese individuals, acting to reduce addictive behaviors, although in each case effect size is modest. For example, some reports document a short-term benefit of fluox-etine and sertraline during the first few weeks of a smoking cessation trial and similar trends in alcohol dependence trials (Covey et al. 2002; Hitsman et al. 1999; Niaura et al. 2002; Cornelius et al. 1999; Naranjo and Knoke 2001; Naranjo et al. 1992). In general however, medications such as SSRIs have not proven to be consistently effective in treating drug abuse and dependence (Walsh and Cunningham 1997). These nonselective serotonergic drugs enhance brain 5-HT function in an indiscriminate fashion, such that 5-HT neurotransmission is increased through all of the various receptor subtypes. This may not always be desirable since different 5-HT receptor subtypes may act in an opposing fashion to modulate neuronal activity and behavioral output. For example, the 5-HT2A receptor appears to modulate aspects of cocaine-induced behaviors and impulsivity in a fashion opposite to the 5-HT2C receptor (Fletcher et al. 2007, 2002; Higgins et al. 2003). As reviewed in this chapter, animal-based work clearly points to the 5-HT2C receptor as a modulator of reward-related behavior. Therefore, compared with nonselective serotonergic agents, 5-HT2C receptor agonists represent a rational and evidence-based (at least from preclinical studies) treatment strategy. Finally, by virtue of subtype selectivity and orthosteric agonist properties, 5-HT2C receptor agonists may activate the 5-HT2C receptor pathway to a greater magnitude than nonselective and indirect 5-HT agonists such as dexfenfluramine and fluoxetine. This may translate into improved efficacy.

With the emergence of positive phase III data for lorcaserin in obesity, and a new drug application (NDA) filing in 2010, it is possible that opportunities to evaluate the therapeutic potential of this compound for drug dependence (e.g. for nicotine or alcohol) could emerge. If lorcaserin is approved for the treatment of obesity, it will likely be followed by several other selective 5-HT2C agonists currently in Phase I/II development, providing further opportunity to evaluate this drug class for treating drug abuse and dependence. Agonists with a superior 5-HT2C versus 5-HT2A/2B selectivity to lorcaserin may allow an even greater magnitude of 5-HT2C receptor activation and potentially efficacy, due to lesser concerns for off-target activity. An even longer term goal may be to find drugs that can modulate RNA editing patterns of 5-HT2C receptors in a manner that may beneficially treat drug dependency states. Whether RNA editing of the 5-HT2C receptor can be therapeutically exploited is an intriguing possibility for future drug discovery (Werry et al. 2008).

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