New endomorphin analogs with mu-agonist and delta-antagonist properties
G. T�th, A. Keresztes, Cs. T�mb�ly, A. P�ter, F. F�l�p, D. Tourw�, E. Navratilova, �. Varga, W. R. Roeske, H. I. Yamamura, M. Szucs, and A. Borsodi
Institute of Biochemistry, Biological Research Center
of Hungarian Academy of Sciences, Szeged, Hungary; University of Szeged,
Hungary; Department of
Organic Chemistry, Vrije University, Brussels, Belgium; University of
Arizona
Health Science Center, Tucson, AZ 85724, USA
Abstract: Endomorphins (endomorphin-1,H-Tyr-Pro-Trp-Phe-NH 2
,endomorphin-2, Tyr-Pro-Phe-Phe-NH2) are potent and selective
µ-opioid receptor agonists. In order to improve the affinity and
chemical stability of endomorphins, we have designed, synthesized,
and characterized novel analogs with unnatural (2 ',6 '-dimethyltyrosine,
Dmt) and/or ß-alicyclic amino acids (ACPC and ACHC). Radioligand
binding assay indicated that several of
the novel analogs exhibit high affinity for both µ-and d-opioid
receptors in rat-or mouse-brain membrane preparations. The most promising
derivativessuch as Dmt-Pro-Trp/Phe-Phe-NH2, Dmt-(1
S,2R)-ACPC-Phe-Phe-NH2, and Dmt-(1S,2R)-ACHC-Phe-Phe-NH2
)were characterized in recombinant cell lines expressing human
µ-or d-opioid receptors. Interestingly, while these novel peptides
were potent opioid agonists in the functional
[35S]GTPgammaS binding assays in Chinese hamster ovary cells
expressing the µ-opioid receptors, some behaved as antagonist
or inverse agonist in the human d-opioid receptor-expressing
CHO cells. Since it has previously been demonstrated that the coadministration
of d-antagonists with µ-analgesics attenuates the development
of analgesic tolerance, introduction of high-affinity
d-antagonist properties into the µ-agonist endomorphins is expected
to lead to potent analgesics that produce limited tolerance.
*Lecture presented at the Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Krak�w, Poland, 15-18 October 2003. Other presentations are published in this issue, pp. 907 -1032.