STRUCTURAL REQUIREMENTS FOR DELTA-OPIOID RECEPTOR-BINDING

  • 1 June 1987
    • journal article
    • research article
    • Vol. 31  (6) , 599-602
Abstract
Structural features influencing opioid activity of enkephalin analogs were investigated through the synthesis and evaluation of opioid receptor binding affinities of a series of cyclic dithioethercontaining analogs and structurally related linear analogs of the cyclic, disulfide-containing peptides, [D-Pen2, D-Pen5]enkephalin and [D-Pen2, L-Pen5]enkephalin, where Pen (penicillamine) is .beta.,.beta.-dimethylcysteine. The major effect of increasing the ring size of the cyclic moiety from disulfide to dithioether analogs was a large decrease in .delta. opioid receptor binding affinity which suggests that relatively compact conformations of the peptide ligand are necessary for optimal binding to this receptor. The effect of bulky, hydrophobic residues at position 2 in the peptide chain was evaluated by preparing the linear analogs, [D-t-Leu2, D-t-Leu5]enkephalin (t-Leu, 2-amino-3,3-dimethylbutanoic acid) and [D-Abu2, D-t-Leu5]enkephalin (Abu, 2-aminobutanoic acid). The former analog was found to be 36- and 450-fold less potent at .delta. and .mu. receptor sites, respectively, than was the latter, suggesting that bulky side chain substituents in position 2 of enkephalin analogs lead to a deleterious steric interaction at .delta. and particularly at .mu. receptors.