Identification of novel neuroprotective agents using pharmacophore modeling.
In addition to its endocrine function, for which it was named, thyrotropin-releasing hormone (TRH) has substantial neuroprotective actions as well as other physiological effects. We have developed a number of modified TRH analogues as well as cyclic dipeptides structurally related to a major metabolic product of TRH, which have enhanced neuroprotective activity but none of the other major physiological effects of TRH. The extensive structure-activity data developed with these compounds were used to develop a pharmacophore model. Subsequently, a web-based pharmacophore searching program was used to query several large three-dimensional databases. Of the 219 compounds identified whose structures met the pharmacophore model, 15 were chosen for study in a classical model of neuronal cell death in vitro; five of these, 2-6, showed neuroprotective activity. Thus, pharmacophore modeling developed from neuroprotective small peptides can be used to identify novel lead compounds as neuroprotective agents.
Faden
Alan I
AI
Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road. N. W., Research Building, Rm. EP12, Washington, DC 20057, USA. fadena@georgetown.edu
Movsesyan
Vilen A
VA
Fang
Xueliang
X
Wang
Shaomeng
S
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents