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

Josue Alfaro-Lopez, Toru Okayama, Keiko Hosohata, Peg Davis, Frank Porreca, Henry I. Yamamura, Victor J Hruby

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

SL-3111 [1-(4-tert-butyl-3'-hydroxy)benzhydryl-4- benzylpiperazine] is a de novo designed, high-affinity and selective nonpeptide peptidomimetic agonist of the δ-opioid receptor. In a previous report we had described the unique biological characteristics of this ligand and also a need for further structural evaluation. To pursue this, we have introduced a completely different heterocyclic template (2 and 3), which, based on molecular modeling studies, may present the required structural features to properly orient the pharmacophore groups. We also have made more subtle changes to the original piperazine scaffold (5 and 11). The biological activities of these compounds revealed an important participation of the scaffold in the ligand-receptor interaction. To further explore functional diversity on the scaffold, we have maintained the original piperazine ring and introduced four different functionalities at position 2 of the heterocyclic ring (15a-d; a = CH2-O-CH2-Ph; b = Me; c = CH2Ph; d = CH2OH). The biological activities observed for these compounds showed a very interesting trend in terms of the steric effects of the groups introduced at this position. A decrease of almost 2000-fold in affinity and potency at the δ- receptor was observed for 15c 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 findings we have realized the importance of this position to further explore and simplify the structure of future generations of peptidomimetic ligands.

Original languageEnglish (US)
Pages (from-to)5359-5368
Number of pages10
JournalJournal of Medicinal Chemistry
Volume42
Issue number26
DOIs
StatePublished - Dec 30 1999

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Peptidomimetics
Opioid Receptors
Structure-Activity Relationship
Ligands
Bioactivity
Scaffolds
Conformations
Molecular modeling
Social Responsibility
Scaffolds (biology)
1-(4-tert-butyl-3'-hydroxybenzhydryl)-4-benzylpiperazine
piperazine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Exploring the structure-activity relationships of [1-(4-(4- tert-butyl-3'-hydroxy)benzhydryl-4-benzylpiperazine] (SL-3111), a high-affinity and selective δ-opioid receptor nonpeptide agonist ligand. / Alfaro-Lopez, Josue; Okayama, Toru; Hosohata, Keiko; Davis, Peg; Porreca, Frank; Yamamura, Henry I.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 42, No. 26, 30.12.1999, p. 5359-5368.

Research output: Contribution to journalArticle

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