title: Identification of novel amino acid derived CCK-2R antagonists as potential antiulcer agent: homology modeling, design, synthesis, and pharmacology.
abstract: The present study revisited the three-dimensional (3D) homology model of CCK-2R using human A(2a) adenosine receptor and the resolved NMR based structure of the third extracellular loop of the CCK-2R as templates. Further in order to identify novel antiulcer agents, rational designing have been performed utilizing the substructure of a well-known CCK-2R antagonist benzotript as a lead molecule and submitted to the combined docking and simulation studies. This led to the understanding of the essential structure requirement as well as variation of binding mode among conformational isomers of small molecule CCK-2R antagonists. In the next step, preparation of each configurational isomer of these molecules was carried out and submitted for their in vitro activity followed by in vivo screening into antiulcer rat model. The biological screening of these compounds has not only validated the developed homology model of CCK-2R but also led to the identification of highly potent CCK-2R antagonist 6a as an orally active and safe candidate molecule having better antiulcer properties than the well-known drug benzotript.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226001, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Gupta
authors.forename: Kanika
authors.initials: K
authors.lastname: Varshney
authors.forename: Neetu
authors.initials: N
authors.lastname: Singh
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Mishra
authors.forename: Mridula
authors.initials: M
authors.lastname: Saxena
authors.forename: Gautam
authors.initials: G
authors.lastname: Palit
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013276:Stomach Ulcer / Q000188:drug therapy*
chemical_list: D000596:Amino Acids; D043887:Receptor, Cholecystokinin B