Peripherally acting enkephalin analogues. 1. Polar pentapeptides.

The design, synthesis, and biological activity of a series of highly polar enkephalin-related pentapeptides are reported. These analogues incorporate structural features that exclude them from the central nervous system and thereby restrict their action to peripherally located receptors. Hydrophilic analogues were obtained by introduction of polar D-amino acid residues at position 2 and, in certain cases, by conversion of the N-terminal amino group of the Tyr residue to a guanidino function. The peptides were synthesized by classical solution methods. All compounds demonstrated in vitro opioid activity in the GPI and all were shown to possess antinociceptive activity in chemically induced writhing models. The analgesic effects were shown to be predominantly peripherally mediated by antagonism of antinociception with the peripheral antagonist N-methylnalorphine. Comparative data obtained in writhing and hot-plate tests were also supportive of a peripheral mode of action. Compound 13a, L-tyrosyl-D-arginylglycyl-L-4-nitrophenylalanyl-L-prolinamide (BW 443C), was identified as having a favorable pharmacological profile, indicating a high level of peripheral selectivity, and worthy of further investigation.