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

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• 作者：Adriano Mollica ; Francesco Pinnen ; Azzurra Stefanucci ; Luisa Mannina ; Anatoly P. Sobolev ; Gino Lucente ; Peg Davis ; Josephine Lai ; Shou-Wu Ma ; Frank Porreca ; Victor J. Hruby
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 11, 2012
• 年：2012
• 卷：55
• 期：19
• 页码：8477-8482
• 全文大小：295K
• 年卷期：v.55,no.19(October 11, 2012)
• ISSN：1520-4804

文摘

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 伪-carbon atoms leads to a meaningful enhancement of the affinity and activity toward 渭 opioid receptors with respect to the prototype compound 9: e.g., 9a, K_i^渭 = 63 nM, GPI (IC₅₀) = 480 nM; 9b, K_i^渭 = 38 nM, GPI (IC₅₀) = 330 nM.