Exploring the structure-activity relationships of [1-(4-tert-butyl-3 '-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective delta-opioid receptor nonpeptide agonist ligand

SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonis t of the delta-opioid receptor. In a previous report we had described the u nique biological characteristics of this ligand and also a need for further structural evaluation(6). To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeli ng studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the ori ginal piperazine scaffold (5 and 11). The biological activities of these co mpounds revealed an important participation of the scaffold in the ligand-r eceptor interaction. To further explore functional diversity on the scaffol d, we have maintained the original piperazine ring and introduced four diff erent functionalities at position 2 of the heterocyclic ring (15a-d; a = CH 2-O-CH2-Ph; b = Me; c = CH2Ph; d = CH2OH). The biological activities observ ed for these compounds showed a very interesting trend in terms of the ster ic effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the delta-receptor was observed for 15 c compared with 15b. This difference may be explained if we postulate that the bioactive conformation of these peptidomimetics is close to the minimal energy conformations calculated in our study. On the basis of these findin gs we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.