De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the δ-opioid receptor

Subo Liao, Josue Alfaro-Lopez, Mark D. Shenderovich, Keiko Hosohata, Jun Lin, Xiaoping Li, Dagmar Stropova, Peg Davis, Kevin A. Jernigan, Frank Porreca, Henry I. Yamamura, Victor J. Hruby

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

On the basis of the structure-activity relationships of δ-opioid- selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained δ- opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the δ-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the δ-opioid receptor over the μ-opioid receptor. Compound 6f (SL3111) showed 8 nM binding affinity and over 2000-fold selectivity for the δ-opioid receptor over the μ-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the δ-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the δ-opioid receptor, which also was observed in the case of the δ-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-C]Phe4]DPDPE on the cloned wild-type and mutated human δ-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((αR)-α(2S,5R)-4-allyl-2,5dimethyl-1- piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), another δ- opioid-selective non-peptide ligand.

Original languageEnglish (US)
Pages (from-to)4767-4776
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number24
DOIs
StatePublished - Nov 19 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Liao, S., Alfaro-Lopez, J., Shenderovich, M. D., Hosohata, K., Lin, J., Li, X., Stropova, D., Davis, P., Jernigan, K. A., Porreca, F., Yamamura, H. I., & Hruby, V. J. (1998). De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the δ-opioid receptor. Journal of Medicinal Chemistry, 41(24), 4767-4776. https://doi.org/10.1021/jm980374r