Biological properties of opioid peptides replacing Tyr at position 1 by 2,6-dimethyl-Tyr

To understand the effect of the replacement of Tyr residue at position 1 in opioid peptides by 2,6-dimethyl-Tyr (Dmt) on the biological property, chir al (D or L) Dmt(1) analogs of Leu-enkephalin (Enk) and Tyr-D-Arg-Phe-beta A la-NH2 (YRFB) were synthesized and their enzymatic stabilities, irt vitro b ioactivities and receptor binding affinities compared with those of parent peptides, [L-Dmt(1)]Enk (1) exhibited 4-fold higher stability against amino peptidase-IM and possessed dramatically increased activities in guinea pig ilium (GPI) (187-fold) and mouse vas deferens (MVD) (131-fold) assays, and in rat brain receptor binding assays (356-fold at mu receptor and 46-fold a t delta receptor) as compared to Enk [L-Dmt(1)]YRFB (3) also exhibited incr eased activities in GPI (46-fold) and MVD (177-fold) assays, and in the bin ding assays (69-fold at mu receptor and 341-fold at delta receptor) as comp ared to the parent peptide. [D-Dmt(1)]Enk (2) and [D-Dmt(1)]YRFB (4) exhibi ted activities with diminished or lesser potency than the parent peptide in all assays. These results indicate that there is a tendency for mu affinit y to be enhanced more than delta affinity with introduction of L-Dmt into d elta ligand peptide (Enk), and for delta affinity to be enhanced more than ill affinity in case of mu ligand peptide (YRFB), resulting in reduced rece ptor selectivities at the receptors.