DE-NOVO DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITIES OF HIGH-AFFINITYAND SELECTIVE NONPEPTIDE AGONISTS OF THE DELTA-OPIOID RECEPTOR

On the basis of the structure-activity relationships of delta-opioid-s elective peptide ligands and on a model of the proposed bioactive conf ormation for a potent and selective, conformationally constrained delt a-opioid peptide ligand [(2S,3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand bind ing assays and in vitro bioassays. The new non-peptide ligands use pip erazine as a template to present the most important pharmacophore grou ps, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of t he D-Pen residues in DPDPE, which has been found to be extremely impor tant for increasing the binding affinity and selectivity of these non- peptide ligands for the delta-opioid receptor over the mu-opioid recep tor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000- fold selectivity for the delta-opioid receptor over the delta-opioid r eceptor. Both enantiomers of SL-3111 were separated, and the (-)-isome r was shown to be the compound with the highest affinity for the delta -opioid receptor found in our study (IC50 = 4.1 nM), with a selectivit y very similar to that observed for the racemic compound. The phenol h ydroxyl group of SL-3111 turned out to be essential to maintain high a ffinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studi es of SL-3111 and [p-C1Phe(4)]DPDPE on the cloned wild-type and mutate d human delta-opioid receptors suggested that the new non-peptide liga nd has a binding profile similar to that of DPDPE but different from t hat of (+)-4-[((alpha allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzy l] -N,N-diethylbenzamide (SNC-80), another; delta-opioid-selective non -peptide ligand.