Arylpiperazine Based Structures

The unsubstituted arylpiperazines mCPP (37) and TFMPP (38) (Fig. 3.4) were among the first nontryptamine 5-HT2C receptor agonists to be identified and still are commonly used as tools to probe 5-HT2C receptor function (Porter et al. 1999). Over the years,

Fig. 3.4 Arylpiperazine-based 5-HT2C receptor agonists

many arylpiperazine based 5-HT2C receptor agonists have been reported (Fig. 3.4). However, the paucity of data does not allow the description of structure-activity relationships. As example, quipazine (39) and MK-212 (40) are nonselective agonists (Porter et al. 1999). ORG-12962 (41) behaves as a partial agonist at human 5-HT2C receptors with low binding selectivity over human 5-HT2A receptors (K. = 12 and 65 nmol/L, respectively). In functional in vitro assays measuring calcium release, 41

displayed pEC50 values of 7.01, 6.38, and 6.28, along with relative efficacies of 62%, 54%, and 41%, at the human 5-HT2C, 5-HT2A, and 5-HT2B receptors, respectively (Leysen and Kelder 1998). Eli Lilly have reported the arylpiperazine-based 5-HT2C receptor agonist LY-448100 (42), which showed high binding affinity (K=9 nmol/L) and was claimed to be 15-fold selective over other 5-HT receptors. LY-448100 (42) behaved as a 5-HT2C receptor agonist with high potency and efficacy (EC50=8 nmol/L, relative efficacy of 110%) (Briner et al. 2001). Also Arena Pharmaceuticals reported a series of arylpiperazine-based 5-HT2C receptor agonists structurally related to mCPP (37). Among these, compound 43 displayed EC50 values of 8 and 529 nmol/L at the 5-HT2C and 5-HT2A receptors, respectively, while it was claimed to be essentially functionally inactive at the 5-HT2B receptor, as determined by measurements of phospho-inositide hydrolysis (Smith et al. 2005). Other arylpiperazine 5-HT2C agonists are 44-46 that possess moderate-to-high binding affinities (K values of 40, 3, and 5 nmol/L, respectively) (Leysen and Kelder 1998; Nilsson and Scobie 2002; Nilsson et al. 2002).

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