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, Kiμ = 63 nM, GPI (IC50) = 480 nM; 9b, Kiμ = 38 nM, GPI (IC50) = 330 nM.

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

MOLLICA, ADRIANO;PINNEN, Francesco Enrico;STEFANUCCI, AZZURRA;
2012-01-01

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 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, Kiμ = 63 nM, GPI (IC50) = 480 nM; 9b, Kiμ = 38 nM, GPI (IC50) = 330 nM.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11564/331287
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