SUBSTITUTION ON THE PHE(3) AROMATIC RING IN CYCLIC DELTA OPIOID RECEPTOR-SELECTIVE DERMORPHIN DELTORPHIN TETRAPEPTIDE ANALOGS - ELECTRONIC AND LIPOPHILIC REQUIREMENTS FOR RECEPTOR AFFINITY

In an effort to explore structural features affecting receptor recognition in a series of conformationally restricted tetrapeptides related to the cyclic, delta-opioid receptor-selective analogue, Tyr-D-Cys-Phe-D-PenOH, electronic, lipophilic, and steric effects at the Phe3 residue were assessed by substitution at different positions of the side-chain aromatic ring by halogens, alkyl, hydroxyl, and nitro groups. Effects on opioid receptor binding affinity and selectivity were determined. The results, which are generally consistent with reports of analogous modifications in linear and cyclic pentapeptide enkephalins, indicate that steric, lipophilic, and electronic properties are all important determinants of delta-opioid receptor recognition. Specifically, modifications which increase lipophilicity or exert electron-withdrawing effects on the aromatic ring enhance binding affinity, while hydrophilic, bulky, or electron-releasing modifications are detrimental. These observations are in excellent agreement with quantitative structure-activity relationship (QSAR) results reported for Phe4 modifications in linear opioid pentapeptide enkephalin analogues, suggesting that the Phe3 tetrapeptide side chain and the Phe4 pentapeptide side chain interact with the same delta-receptor binding subsite.