CoMFA Studies Of Endomorphin-2 Analogues

Endomorphin-1(Tyr-Pro-Trp-Phe-NH₂ EM-1)and endomorphin-2(Tyr-Pro-Phe-Phe -NH₂,EM-2)are highly potent and selective endogenous ligands toμ-opioid receptor. Although they are the most small model peptides to reveal the function of opioid ligands, EMs were found to be easily digested by enzymes and hard to pass the blood-brain-barrier. To develop potent analogies with less side effects,many group have reported different methods to develop the more ideal analogs of EMs.However,their structure-activity relationship remains unclear,and no significant preference for subtype opioid receptor has been achieved.In order to find new EM-2 analogs with superior property that target theμ-receptor, three-dimensional quantitative structure and activity relationship(3D-QSAR)studies were performed on 21 EM-2 analogs using comparative molecular field analysis(CoMFA).To obtain statistically significant and robust CoMFA models,21 EM-2 analogues were assembled by pooling biological and structural data from independent studies.The best predictive model for theμ-receptor were obtained with q2=0.634,r2=0.970.The models were further validated by a test set containing six compounds.Based on the model,several candidate structures were designed and predicted for thwir binding potencies.This study provides helpful information for designing new categoryμ-agonists from EMs.