In vitro activity profiles of cyclic and linear enkephalin pseudopeptide analogs.
The peptide bond in the 4-5 position of the cyclic and linear enkephalin analogs H-Tyr-cyclo[-D-Lys-Gly-Phe-L(or D)-Leu-] and H-Tyr-D-Ala-Gly-Phe-L(or D)-Leu-OH was replaced by a thiomethylene ether linkage. Each of the configurational isomers of the cyclic pseudopeptide H-Tyr-cyclo[-D-Lys-Gly-Phe psi [CH2S]L(or D)-Leu-] showed high potency in both the guinea pig ileum and the mouse vas deferens assay and, therefore, had no preference for either mu- or delta-opioid receptors, in contrast to the cyclic parent peptides H-Tyr-cyclo[-D-Lys-Gly-Phe-L(or D)-Leu-] which are mu-receptor selective. The loss of selectivity observed with the cyclic pseudopeptides may be due to the greater flexibility of their 18-membered ring structures as a consequence of the peptide bond substitution. The linear pseudopeptide analogs were both less potent and less delta-receptor selective than their parent compounds. These results indicate that thiomethylene ether peptide bond replacements can have a pronounced effect on the activity profile of peptide hormones and neurotransmitters.
D000818:Animals; D001681:Biological Assay; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000502:physiology
D004745:Enkephalins; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; C048759:tyrosyl-alanyl-glycyl-phenylalanyl-psi(thiomethylene)leucine; C048758:tyrosyl-cyclo(lysyl-glycyl-phenylalanyl-psi(thiomethylene)leucine); D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine