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The constitutional similarity with different secondary structure preference between the Aba-Gly and the spiro-Aba-Gly scaffolds were exploited to design the novel endomorphin-2 analogs Tyr-spiro-(R/S)-Aba-Gly-Phe-NH₂ (1 and 2) and Tyr-(R/S)-Aba-Gly-Phe-NH₂ (3 and 4). The (R)-spiro analog 1 was found to be a potent and selective μ-opioid agonist/partial agonist (K_iμ = 29.3 nM, IC₅₀ = 50 nM, K_e = 0.57). NMR experiments and molecular modeling indicated that its backbone adopts mainly a β-turn in aqueous solution.