Design of chimeric molecules based on two distinct classes of opioid ligands, the peptide portion derived from enkephalins and the non-peptide moiety from a 4-anilidopiperidines series, holds numerous possibilities in the area of drug design, and their medicinal applications. Fentanyl is a highly potent and clinically widely used m-selective analgesic for relief of severe acute and chronic pain, but its use is limited due to side effects.The inherent m-opioid receptor selectivity of fentanyl and its analogues allows introduction of m-selectivity into corresponding opioid peptide analogues. The designed analogues (Scheme 1) were prepared in good yields by solid phase synthesis via attachment to the side chain of glutamic acid using Fmoc/Boc chemistry and tested for in vitro opioid activity. The results of our biological tests show that substitution of the propionyl moiety of fentanyl with opioid peptide ligands leads to compounds possessing high affinity for opioid receptors. The dimeric nature of fentephalines is responsible for their extraordinary pharmacological profile. The work is supported by grants from the US Public Health Service, National Institute of Drug Abuse.