Ring Size in Octreotide Amide Modulates Differently Agonist versus Antagonist Binding Affinity and Selectivity

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• 作者：Christy Rani R. Grace ; Judit Erchegyi ; Manoj Samant ; Renzo Cescato ; Veronique Piccand ; Roland Riek ; Jean Claude Reubi ; Jean E. Rivier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 8, 2008
• 年：2008
• 卷：51
• 期：9
• 页码：2676 - 2681
• 全文大小：703K
• 年卷期：v.51,no.9(May 8, 2008)
• ISSN：1520-4804

文摘

H-DPhe²-c[Cys³-Phe⁷-DTrp⁸-Lys⁹-Thr¹⁰-Cys¹⁴]-Thr¹⁵-NH₂ (1) (a somatostatin agonist, SRIF numbering) and H-Cpa²-c[DCys³-Tyr⁷-DTrp⁸-Lys⁹-Thr¹⁰-Cys¹⁴]-Nal¹⁵-NH₂ (4) (a somatostatin antagonist) are based on the structure of octreotide that binds to three somatostatin receptor subtypes (sst_2/3/5) with significant binding affinity. Analogues of 1 and 4 were synthesized with norcysteine (Ncy), homocysteine (Hcy), or D-homocysteine (DHcy) at positions 3 and/or 14. Introducing Ncy at positions 3 and 14 constrained the backbone flexibility, resulting in loss of binding affinity at all sst_s. The introduction of Hcy at positions 3 and 14 improved selectivity for sst₂ as a result of significant loss of binding affinity at the other sst_s. Substitution by DHcy at position 3 in the antagonist scaffold (5), on the other hand, resulted in a significant loss of binding affinity at sst₂ and sst₃ as compared to the different affinities of the parent compound (4). The 3D NMR structures of the analogues in dimethylsulfoxide are consistent with the observed binding affinities.