Serotonin 5HT2C receptor agonists

The serotonin (5-HT) receptor family are among the most studied of the neurotransmitters. The 5-HT2C receptor subclass has seen a great deal of research during the past 10 years, and evidence has established the potential as a target for treating anxiety, depression [107], schizophrenia [108,109] and most notably obesity [110,111]. Until recently, attaining selectivity in the 5-HT2C receptor subclass over the closely related 5-HT2A and 5-HT2B receptors had been elusive, but selective agents are now emerging [112]. The rational for the use of selective 5-HT2C agonists in the treatment of schizophrenia is based upon the ability of 5-HT2C receptor activation to reduce dopamine neurotransmission in the mesolimbic system, and the potential to reduce side effects mediated by current antipsychotics such as weight gain [113].

Several noteworthy reports in the area of schizophrenia research have recently appeared. The tetracyclic indole derivative WAY-163909 (45) has been established in

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the literature as a potent and selective agonist (5-HT2C K = 10.5 nM, EC50 = 8 nM; 5-HT2B K = 485nM, EC50 = 185nM; 5-HT2A K = 212nM, EC50 = no effect) [114]. Recent reports from Wyeth on the activity of 45 in antipsychotic models include activity in rat conditioned avoidance assay (ID50 = 1.3mg/kg), mouse PCP-induced hyperactivity (0.1mg/kg) and MK-801-induced disruption of prepulse inhibition (MED = 5.4mg/kg). Additionally, at doses up to 30mg/kg 45 showed no cataleptic potential in mouse. Taken together these data suggest the potential utility of a 5-HT2C receptor agonist as an atypical antipsychotic. Several additional reports of 5-HT2C ligands have been reported in the literature in the past year. Researchers at Vernalis reported indole 46 to be a full 5-HT2C agonist with good potency (K = 1.6 nM, EC50 = 2.9 nM (99% efficacy)) with modest selectivity over the 5-HT2A and 5-HT2B receptors (5-HT2A K = 31 nM, EC50 = 32nM (88% efficacy) and 5-HT2B K = 12 nM, EC50 = 1.1 nM (65% efficacy)) [115]. The pyrroloisoquino-line VER-2692 (47) is reported to be a potent 5-HT2C ligand (K = 1.6 nM) with modest selectivity over the 5-HT2A and 5-HT2B receptors (K = 31 and 12 nM, respectively), and in vivo activity at 3mg/kg in a feeding model [116].

WAY-163909 (45)

WAY-163909 (45)

NH2 VER-2692 (47)

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