cis-4-Amino-L-proline Residue as a Scaffold for the Synthesis of Cyclic and Linear Endomorphin-2 Analogues: Part 2

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 cis-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 9: e.g., 9a, Ki μ = 63 nM, GPI (IC50) = 480 nM; 9b, Ki μ = 38 nM, GPI (IC50) = 330 nM