Novel, delta-opioid receptor-selective peptide antagonists: demonstration of a possible opioid interaction in the absence of a protonated nitrogen and attempts to locate the protonated nitrogen site.
We have recently (Rónai et al., 1992) introduced a family of novel delta-opioid receptor-selective peptide antagonists, based on the Tyr-Pro-Gly-Phe-Leu-Thr structure, where the nitrogen accepts substituents that make protonation possible (e.g. diallyl) as well as substituents (e.g. t-Boc) where protonation cannot occur. In this paper, we present the details of a design strategy where the structurally closely related biologically active and inactive compounds are suggestive of conformational requirements of action. Furthermore, since even those derivatives of the antagonist peptides where the N-terminus was free were either devoid of opioid agonist activity or were extremely weak agonists, it is suggested that these antagonists do not interact with the conventional "opioid nitrogen site". To find this "conventional" site, a number of N-substituted (phenylglycyl-, alpha-Boc-lysyl-, alpha-Phe-beta-alanyl-) derivatives of Tyr-Pro-Gly-Phe-Leu-Thr hexapeptide were synthesized and their biological activities were determined in the mouse vas deferens bioassay.
Rónai
A Z
AZ
Institute of Organic Chemistry, L. Eötvös University, Budapest, Hungary.
Botyánszki
J
J
Magyar
A
A
Borsodi
A
A
Benyhe
S
S
Medzihradszky
K
K
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000187:drug effects*; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009584:Nitrogen / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D014649:Vas Deferens / Q000187:drug effects*
D017465:Receptors, Opioid, delta; D009584:Nitrogen