Record number :
1300884
Title of article :
The high affinity melatonin binding site probed with conformationally restricted ligands—I. Pharmacophore and minireceptor models Original Research Article
Author/Authors :
Johanna M. Jansen، نويسنده , , Swier Copinga، نويسنده , , Gert Gruppen، نويسنده , , Eduardo J. Molinari، نويسنده , , Margarita L. Dubocovich، نويسنده , , Cor J. Grol، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 1996
Pages :
12
From page :
1321
To page :
1332
Abstract :
The affinities of enantiomers of conformationally restricted melatonin analogues for the ML-1 and ML-2 putative melatonin receptor subtypes are reported. Most ligands exhibited reversed stereoselectivity when competing with 125I 2-iodomelatonin binding to chicken retinal (ML-1) and hamster brain (ML-2) membranes, further supporting the biochemical and pharmacological differences reported for these two sites. Based on the data for the ML-1 site and thorough conformational analyses of several ligands, two pharmacophore models were derived using the program APOLLO. The pharmacophoric elements included were putative receptor points from the amide NH, the amide CO, and the methoxy-O, together with the normal through the phenyl ring. The large drop in ML-1 affinity observed for 4-methoxy-2-acetamido-indan (6a) could not be explained from either of these models. Minireceptors were subsequently built around the two pharmacophores using Yak. Analysis of the resulting ligand-minireceptor interactions offered an explanation for the low affinity of 6a and allowed one of the pharmacophore models to be selected for use in future drug design.
Journal title :
Bioorganic and Medicinal Chemistry
Link To Document :