Design of opioid peptides for a potential delta-receptor affinity label function: comparison with the mu-specific Tyr-D-Ala-Gly-(Me)Phe-chloromethyl ketone.
To find a delta-opioid receptor preferring peptide structure containing an Asp residue in a potentially interacting position, Tyr-Pro-Phe-Asp, Tyr-D-Ala-Phe-Asp, Tyr-D-Ala-Gly-Phe-Asp, Tyr-D-Ala-Gly-Phe-Asp alpha- and beta-methyl ester and Tyr-Gly-Gly-Phe-Asp peptides were synthesized and their biological activities were analyzed in vitro in mouse vas deferens and longitudinal muscle strip of guinea pig ileum. Changing the beta-methyl ester for an alkylating chloromethyl ketone moiety in the delta-receptor-selective agonist Tyr-D-Ala-Gly-Phe-Asp-beta-methyl ester enhanced further the delta-receptor preference. The delta-receptor selective chloromethyl ketone but not the beta-methyl ester gave a very slow washout after prolonged incubation in the mouse vas deferens bioassay; however, it was still readily displaceable by naloxone. The washout pattern of mu-specific Tyr-D-Ala-Gly-(Me)Phe chloromethyl ketone did not differ in the bioassays from that of the corresponding Gly5-ol derivative. Both chloromethyl ketones gave irreversible characteristics in the receptor binding assay.
Rónai
A Z
AZ
Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Szeged.
Hepp
J
J
Magyar
A
A
Borsodi
A
A
Medzihradszky
K
K
D000345:Affinity Labels; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000345:Affinity Labels; D000590:Amino Acid Chloromethyl Ketones; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C052900:tyrosyl-alanyl-glycyl-N(alpha)-methylphenylalanine chloromethyl ketone