title: 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 beta(3)-adrenergic receptor agonists, a series of novel substituted 1,2,3,4-tetrahydroquinolin-6-yloxypropanes has been synthesized and evaluated for their beta(3)-adrenergic receptor agonistic activity (ranging from -17.73% to 90.64% inhibition at 10 microM) using well established Human SK-N-MC neuroblastoma cells model. Four molecules viz. 11, 15, 22 and 23 showed beta(3)-AR agonistic IC(50) value of 0.55, 0.59, 1.18 and 1.76 microM, respectively. These four candidates have been identified as possible leads for further development of beta(3)-adrenergic receptor agonists for obesity and Type-II diabetes pharmacotherapy. The free OH and NH functions are found to be essential for beta(3)-adrenergic receptor agonistic activity. Among the synthesized beta(3)-adrenergic receptor agonists having 1,2,3,4-tetrahydroquinoline scaffold, the N-benzyl group is found to be superior over N-arylsulfonyl group. A putative pharmacophore model has been modeled considering the above four active molecules which distinguishes well between the active and inactive molecules.
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Shakya
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000322:Adrenergic Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009447:Neuroblastoma / Q000473:pathology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D011804:Quinolines