Synthesis and biological activity of linear and cyclic enkephalins modified at the Gly3-Phe4 amide bond.
As part of our continuing effort to define structure-activity relationships for enkephalin and design enzymatically resistant analogs, we report the synthesis and biological activities of linear and cyclic enkephalin analogs modified at the Gly3-Phe4 amide bond. The partial retro-inverso enkephalin analog Tyr-D-Ala-gGly-(R,S)-mPhe-Leu-NH2 and its cyclic counterpart, Tyr-cyclo[D-A2 bu-gGly-(R,S)-mPhe-Leu-], were synthesized as diastereomeric mixtures using solution methodology. The racemic benzylmalonate allowed the linear analog to be synthesized by fragment coupling at the reversed bond. Cyclization of the second analog was carried out at high concentration, eliminating formation of polymer by the use of an insoluble base. All gem-diaminoalkyl residues were prepared by conversion of peptidyl amides with benzene iodonium bis(trifluoroacetate). Diastereomers of both compounds were separable by reverse phase HPLC but those of the linear compound racemized rapidly under conditions of testing and were therefore tested together. All analogs tested had activities ranging from 6 to 14% of the activity of Leu enkephalin, indicating that the Gly3-Phe4 amide bond is important, though not crucial, for receptor binding.
Richman
S J
SJ
Goodman
M
M
Nguyen
T M
TM
Schiller
P W
PW
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004743:Enkephalin, Leucine / Q000494:pharmacology; D004745:Enkephalins / Q000138:chemical synthesis* / Q000494:pharmacology; D005998:Glycine; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009904:Optical Rotation; D010649:Phenylalanine; D011957:Receptors, Opioid / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004745:Enkephalins; D007202:Indicators and Reagents; D011957:Receptors, Opioid; D010649:Phenylalanine; D004743:Enkephalin, Leucine; D005998:Glycine