Potential Clinical Applications

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Obesity - The role of the 5-HT2c receptor in regulation of appetite is based on several keys lines of evidence. First, the 5-HT2c receptor is enriched in nuclei of the hypothalamus that regulate satiety. 5-HT2C agonists inhibit food intake even after chronic administration in rodents (34,35). Whereas selective antagonists block these effects, paradoxically, they alone do not increase food intake and weight gain (12,36,37). 5-HT2C "knockout" mice developed delayed-onset obesity and hyper-insulinemia, and are insensitive to the hypophagic effects of fenfluramine (38,39). Finally, nonselective 5-HT2c agonists reduce food intake and weight in humans (40).

Fenfluramine, at least partly, owes its anorectic actions (via 5-HT release and blockade of 5-HT re-uptake) to stimulation of 5-HT2c receptors, whereas its major metabolite norfenfluramine is a potent 5-HT2C agonist (41,42). Fenfluramine was removed from the U.S. market in 1997 because of its association with an increased incidence of valvular heart disease (VHD). It had been also associated with an increased risk for developing primary pulmonary hypertension (PPH). Because of the paucity of the 5-HT2C receptors in peripheral tissues, the 5-HT2c receptor is unlikely involved with these illnesses. Fenfluramine's ability to serve as a 5-HT transporter substrate is hypothesized to contribute to PPH whereas the mitogenic 5-HT2b agonist properties of norfenfluramine have been implicated in VHD (43-45). Selective 5-HT2c agonists, devoid of these cross-reactive interactions, hold the prospect of being safe and therapeutically effective agents for the long-term treatment of obesity. For additional information on role of GPCR modulators in treatment of obesity, see Chapter 1 of this volume.

Epilepsy - Epilepsy refers generically to a multiplicity of many distinct disorders characterized by recurrent seizures resulting from massive neuronal discharge. Support for the potential utility of 5-HT2c agonists as anti-epileptic medicines is afforded by the discovery that 5-HT2C "knockout" mice exhibit sporatic spontaneous seizures characterized by lower focal seizure thresholds, increased focal seizure excitability, and facilitated propagation within the forebrain (46,47). Wild-type mice recapitulated the mutant phenotype when pre-treated with a nonselective 5-HT2c antagonist prior to electro-shock testing. Pharmacological studies in rodents also suggest that stimulation of 5-HT2C receptors with a nonselective 5-HT2C agonist affords seizure protection, which can be attenuated by pre-treatment with a 5-HT2c/2b antagonist (48).

Schizophrenia - Atypical antipsychotic drugs are more effective than typical antipsychotic drugs in treating negative symptoms of schizophrenia, while producing fewer extra-pyramidal side effects. The potential contribution of the 5-HT2C receptor to the "atypical" profile is suggested because these drugs exhibit moderate-to-high affinities (49) and inverse agonist properties for the receptor (50). The 5-HT2c receptor also regulates cortical and sub-cortical dopamine (DA) function (51). 5-HT2c agonists inhibit mesolimbic DA but not nigrostriatal function, whereas antagonists have the converse effect. To the extent that reduced mesocorticolimbic DA function has been hypothesized in schizophrenia (52), disinhibition of this pathway by 5-HT2c antagonists/inverse agonists may underlie the unique effects of atypical agents on ameliorating negative symptoms of this disease (50).

Anxiety Disorders - 5-HT2c antagonists have shown anxiolytic activity in several animal models (53-55). Interestingly, 5-HT2c agonists have also shown activity in models of panic and obsessive-compulsive disorder, two types of anxiety disorders in humans (56,57). Clinical support for the 5-HT2C mechanism is provided by a recent report that deramciclane (vide infra) was efficacious and well-tolerated in a controlled Phase 2 trial in GAD patients (58). 5-HT2C agonists/antagonists may also be useful for the treatment of depression as suggested by some preclinical animal models, and the known disinhibitory role of 5-HT2c antagonists on mesolimbic DA function (51,57).


The close sequence homology among members of the 5-HT2 receptor subfamily has made identification of agonists selective for the 5-HT2c receptor subtype a formidable challenge. Further complicating this area is the existence of multiple RNA edited isoforms, different sources of receptor (e.g, rat vs human), and different methods for determining ligand affinities (e.g., agonist vs. antagonist radioligands). These factors combine to make comparisons of 5-HT2c affinities and selectivities reported across different laboratories a difficult endeavor. For example, a series of isotryptamines has been reported to contain full agonists at the 5-HT2C receptor with excellent selectivity over 5-HT2A receptor (59). The difluoroindole 1 reportedly possessed potent 5-HT2c affinity (Ki =1 nM) and 100-fold selectivity versus the 5-HT2a- receptor. Re-examination of the binding profile of I from another laboratory, however, indicated that the 5-HT2A/5-HT2C receptor selectivity was at best only 10fold (60). This discrepancy is likely the result of the initial data being derived using antagonist radioligands as opposed to the more appropriate to use of agonist radioligands that label the agonist high-affinity state of the receptor (60). Whether inspired by 1 or not, much of the recent activity in the search for selective 5-HT2C agonists that is described below has focused on tryptamine and isotryptamine derivatives.

Indazoles such as 2 and 3 have recently been claimed as 5-HT2c agonists useful as anti-obesity agents. Compound 2 is reported to have a 5-HT2C Ki of 37 nM (61) and an efficacy (relative to 5-HT) of 81 % (ECso = 8 nM). This compound is nonselective, however, displaying affinity for the 5-HT2b receptor (47 nM) and is a partial agonist at 5-HT2A (48% efficacy, EC50 = 285 nM). Compound 3 is a partial agonist at both 5-HT2C and 5-HT2A receptors with efficacies of 51% (EC50 = 55 nM) and 46% (ECso = 346 nM), respectively (62).

A number of tricyclic tryptamine and isotryptamines have also been reported recently. The isotryptamine compounds 4 and 5 are claimed as direct acting 5-HT2 receptor ligands for use in therapy, particularly as anti-obesity agents (63). Compound 4 is a potent 5-HT2c agonist (Ki = 19 nM, 72% efficacy) but displays poor selectivity relative to either 5-HT2A (Ki = 48 nM) or 5-HT2B (Ki = 31 nM). Improved 5-HT2c/5-HT2a selectivity was achieved in this series by halogen substitution on the aromatic ring (a recurring strategy across templates), although this resulted in an interesting switch of absolute stereochemistry for the more potent isomer from (R) to (S). The fluoro analog 5 is reported to possess over 8-fold selectivity for 5-HT2c over 5-ht2a receptors (Ki values = 65 nM vs 550 nM, respectively). However, 5 still exhibits significant potency at 5-HT2b receptors (Ki = 161 nM). The closely related tryptamine 6 displayed levels of affinity, selectivity, and efficacy similar to 5 when tested as the racemate (Ki values, 5-HT2C = 81 nM, 5-HT« = 448 nM; 5-HT2B 122 nM; 69% efficacy)(64). Azatryptamine compounds such as 7 have also been reported recently, but no biological data were disclosed (65).

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