Substituted 1, 2, 3, 4-Tetrahydroquinolin-6-yloxypropanes as beta3-adrenergic receptor agonists: Design, synthesis, biological evaluation and pharmacophore modeling

Abstract

In search of potent beta3-adrenergic receptor agonists, a series of novel substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes has been synthesized and evaluated for their beta3-adrenergic receptor agonistic activity (ranging from -17.73% to 90.64% inhibition at 10 micro M) using well established Human SK-N-MC neuroblastoma cells model. Four molecules viz. 11, 15, 22 and 23 showed beta3-AR agonistic IC50 value of 0.55 microM, 0.59 microM, 1.18 microM and 1.76 microM respectively. These four candidates have been identified as possible leads for further development of beta3-adrenergic receptor agonists for obesity and Type-II diabetes pharmacotherapy. The free OH and NH functions are found to be essential for beta3-adrenergic receptor agonistic activity. Among the synthesized beta3-adrenergic receptor agonists having 1,2,3,4-tetrahydroquinoline scaffold, the N-benzyl group is found to be superior over N-arylsulphonyl group. A putative pharmacophore model has been modeled considering the above four active molecules which distinguishes well between the active and inactive molecules.