<i>cis</i>-4-Amino‑l‑proline Residue As a Scaffold for the Synthesis of Cyclic and Linear Endomorphin‑2 Analogues: Part 2

Abstract

Recently, we reported synthesis and activity of a constrained cyclic analogue of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH₂) and related linear models containing the <i>cis</i>-4-amino-l-proline (cAmp) in place of native Pro². In the present article, the adopted rationale is the possible modulation of the receptor affinity of the cAmp containing EM-2 analogues by assigning a different stereochemistry to the Phe³ and Phe⁴ residues present in the ring. Thus, eight more analogues with different absolute configuration at the chiral center of the aromatic residues in positions 3 and 4 have been synthesized and their opioid activity examined. The stereochemical change at the α-carbon atoms leads to a meaningful enhancement of the affinity and activity toward μ opioid receptors with respect to the prototype compound <b>9</b>: e.g., <b>9a</b>, <i>K</i>_<i>i</i>^μ = 63 nM, GPI (IC₅₀) = 480 nM; <b>9b</b>, <i>K</i>_<i>i</i>^μ = 38 nM, GPI (IC₅₀) = 330 nM