Hexahydro derivative of (D-Met2, Pro-NH2(5)]-enkephalin gives rise to physical dependence

Filippi et al. (1979) have claimed that substitution of cyclohexylalanine for phenylalanine in leucine-enkephalin and its L-Ser3 derivative resulted in synthetic analogs which were non-addicting. We have examined the hexahydro derivative of [D-Met2, Pro-NH2(5)]-enkephalin, a potent analgesic agent, to determine if dependence liability can be separated from short-term opiate actions after hydrogenation of the phenylalanine residue. In contrast to Filippi et al.'s observations, we found that the hexahydro derivative of [D-Met2, Pro-NH2(5)]-enkephalin gives rise to physical dependence and that its short-term potencies generally paralleled its long-term ability to produce physical dependence.