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Novel endomorphin-2 (EM-2) analogs have been synthesized, incorporating unnatural amino acids with six-membered heterocyclic rings, such as piperidine-2-, 3- and 4-carboxylic acids (Pip, Nip and Inp, respectively) instead of Pro in position 2. [( R)-Nip2]EM-2 displayed an extremely high affinity for the μ-opioid receptor with IC50 = 0.04 ± 0.01 nm in comparison with IC50 = 0.69 ± 0.03 nm for EM-2. This analog was also very potent in the aequorin luminescence-based functional calcium assay and showed significantly enhanced stability in rat brain homogenate. [ABSTRACT FROM AUTHOR]

Endomorphins, endogenous μ-opioid receptor ligands, have been shown to exert antinociceptive, antidepressant, anxiolytic, and neuromodulatory effects, as well as to influence cardiovascular, respiratory, and gastrointestinal systems. In the present study, we designed and synthesized a series of tetrapeptides and tripeptides (amides and peptide acids) of similar to endomorphins structure, but with low μ-opioid receptor affinity, and tested them as possible inhibitors of endomorphin-degrading enzymes. The obtained results indicate that the tripeptides Tyr-Pro-Ala-NH2 and Tyr-Pro-Ala-OH, which do not bind to the μ-opioid receptors, are potent inhibitors of endomorphin-degrading enzymes in the rat brain. We suggest that the in vivo administration of these novel analogs may enhance physiological effects of endogenous endomorphins by decreasing the rate of their enzymatic cleavage. [ABSTRACT FROM AUTHOR]