<i>cis</i>-4-Amino‑l‑proline Residue As a Scaffold for the Synthesis of Cyclic and Linear Endomorphin‑2 Analogues: Part 2
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Abstract
Recently, we reported synthesis and activity of a constrained
cyclic analogue of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH<sub>2</sub>) and related linear models containing the <i>cis</i>-4-amino-l-proline (cAmp) in place of native Pro<sup>2</sup>. 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 Phe<sup>3</sup> and Phe<sup>4</sup> 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><sub><i>i</i></sub><sup>μ</sup> = 63 nM,
GPI (IC<sub>50</sub>) = 480 nM; <b>9b</b>, <i>K</i><sub><i>i</i></sub><sup>μ</sup> = 38 nM, GPI (IC<sub>50</sub>) = 330 nM