Conformational flexibility of serotonin1A receptor ligands from crystallographic data. Updated model of the receptor pharmacophore.
Preparation and affinity to 5-HT1A and 5-HT2A receptors of new buspirone analogues 7-17 are reported. The compounds possess high to low affinity to 5-HT1A and moderate to low to 5-HT2A receptors. The crystal structures have been determined for compounds 11, 12, 13, and 14. For low affinity ligand (15) of 5-HT1A receptor conformational analysis was performed and compared with similar analyses performed for know high (buspirone 1) and very high (WY-48,723 2) affinity ligands of the receptor. Structure-activity relationship is discussed for the affinity to 5-HT1A receptor. A three-point pharmacophore explaining interactions of buspirone-like molecules with the receptor binding site is proposed.
Chilmonczyk
Z
Z
Pharmaceutical Research Institute, Warszawa, Poland.
Szelejewska-Wozniakowska
A
A
Cybulski
J
J
Cybulski
M
M
Koziol
A E
AE
Gdaniec
M
M
D000818:Animals; D001665:Binding Sites; D002065:Buspirone / Q000737:chemistry* / Q000378:metabolism; D003461:Crystallography; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D002065:Buspirone