NEWLY DISCOVERED STEREOCHEMICAL REQUIREMENTS IN THE SIDE-CHAIN CONFORMATION OF DELTA-OPIOID AGONISTS FOR RECOGNIZING OPIOID DELTA-RECEPTORS

Topographic design of peptide ligands using specialized topographicall y constrained amino acids can provide new insights into the stereochem ical requirements for delta opioid receptors. A highly constrained tyr osine derivative, (2S,3S)-beta-methyl-2',6'-dimethyltyrosine [(2S,3S)- TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen( 2),D-Pen(5)] enkephalin (delta(1)) and Deltorphin I (delta(2)). The re sults of binding assays and bioassays showed that the two analogues (3 and 4) acted very differently at delta opioid receptors. Further phar macological evaluations suggested that they actually interact primaril y with the delta(1) and delta(2) receptor subtypes, respectively. Thes e results, and conformational studies using NMR and computer-assisted modeling, provided insights into the different stereochemical requirem ents for these two delta opioid ligands to recognize the delta opioid receptor and its subtypes.