(2001b). The amine portion of the ethanolamine group was attached to the central aryl fragment by a two- or three-carbon atom spacer. The central aryl linker fragment was replaced by a benzene (Naylor et al., 1998) or indole moiety (Harada et al., 2003). The central aromatic #selleck compound randurls[1|1|,|CHEM1|]# region was linked to the sulfonamide group, which is understood to be essential for selectivity
of β3-AR agonistic activity (Uehling et al., 2002). Various research groups introduced acidic functionality on R2 to increase the selectivity for β3-AR activity. In addition, they suggested that the steric bulk of the R2 substituent also contributed to the potency and selectivity of β3-AR agonists. However, it is thought that introduction of such hydrophilic groups may generally cause low oral bioavailability, partly due to poor absorption (van de Waterbeemd et al., 2001). Numbers of various bulky fragments attached to R2 have been
reported. These fragments are long chains with oxadiazolidinedione (Hu et al., 2001d), thiazolidinediones (Hu et al., 2001a), urea (Ashwell et al., 2001), triazole (Brockunier et al., 2000), oxazole (Ok et al., 2000), oxadiazole (Feng et al., 2000; Biftu et al., 2000), thiazole (Mathvink et al., 2000), etc. Scheme 1 Essential pharmacophore elements present in β3-AR agonists, as identified from the reported β3-selective arylethonolamine/aryloxypropanolamine derivatives Molecular modeling studies offer several valuable tools for understanding the interactions of drugs and their receptors on a molecular Mirabegron level (Silverman, 2004). In the case of β-ARs very few molecular modeling studies have PKC412 purchase appeared to date. This is mainly due to the absence of three-dimensional (3D) information
about these receptors. Some bold attempts have been made to computationally model the 3D structure of these targets. Lybrand et al. reported 3D models for agonist and antagonist complexes with β-adrenoceptors using computer modeling techniques (Kontoyianni et al., 1996; Furse and Lybrand, 2003). Saxena and coworkers reported 3D quantitative structure–activity relationship (QSAR) studies on a cyclic ureidobenzenesulfonamides series of molecules using the Apex-3D method (Kashaw et al., 2003; Prathipati and Saxena, 2005), and comparative molecular field analysis (CoMFA) and CoMSIA for different therapeutic areas (Gyanendra et al., 2004; Stuti et al., 2004). Recently, we reported CoMFA studies on a 4-aminomethylpiperidine series of β3-AR agonists (Kumar and Bharatam, 2005). In this paper we report comparative studies on the molecular field requirements for a tryptamine based series of molecules toward β1-, β2-, and β3-ARs. Kato and coworkers reported the relative biological activities of tryptamine-based agonists toward β1-, β2-, and β3-ARs and pointed out that the compounds may be more specific to β3-ARs (Mizuno et al., 2004, 2005; Sawa et al., 2004, 2005).