Enkephalin analogs: synthesis and properties of analogs with lipophilic or extended carboxyl-terminus. Quantitative structure-activity relationship of analogs modified in residue position 5

Four analogs of enkephalin (EK) have been synthesized by the solid-phase method and their biological activities have also been investigated. All four analogs were less active than Met-enkephalin (Met-EK) as shown by relative potencies in the guinea pig ileum (GPI) assay: Met-EK, 100; [Phe5]-EK-NH2, 59; [Trp5]-EK-NH2, 11; Met-EK-Cys(Cam)-OH, 37; and N, N'-bis(Met-EK)-cystine, 34. Two of the analogs were more potent than Met-EK as shown by relative potencies in the mouse tail-flick assay for analgesia: Met-EK, 100; [Phe5]-EK-NH2, 1340; [Trp5]-EK-NH2, 1640. Quantitative structure-activity relationship calculations were carried out for GPI potencies of analogs substituted in position 5. The calculation indicated that, in this position, the bulkiness had the main influence.