Novel, Potent, and Radio-Iodinatable Somatostatin Receptor 1 (sst1) Selective Analogues

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• 作者：Judit Erchegyi ; Renzo Cescato ; Christy Rani R. Grace ; Beatrice Waser ; Vronique Piccand ; Daniel Hoyer ; Roland Riek ; Jean E. Rivier ; Jean Claude Reubi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：2733-2746
• 全文大小：342K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

The proposed sst₁ pharmacophore (J. Med. Chem. 2005, 48, 523−533) derived from the NMR structures of a family of mono- and dicyclic undecamers was used to design octa-, hepta-, and hexamers with high affinity and selectivity for the somatostatin sst₁ receptor. These compounds were tested for their in vitro binding properties to all five somatostatin (SRIF) receptors using receptor autoradiography; those with high SRIF receptor subtype 1 (sst₁) affinity and selectivity were shown to be agonists when tested functionally in a luciferase reporter gene assay. Des-AA^{1,4−6,10,12,13}-[DTyr²,DAgl(NMe,2naphthoyl)⁸,IAmp⁹]-SRIF-Thr-NH₂ (25) was radio-iodinated (¹²⁵I-25) and specifically labeled sst₁-expressing cells and tissues. 3D NMR structures were calculated for des-AA^{1,4−6,10,12,13}-[DPhe²,DTrp⁸,IAmp⁹]-SRIF-Thr-NH₂ (16), des-AA^{1,2,4−6,10,12,13}-[DAgl(NMe,2naphthoyl)⁸,IAmp⁹]-SRIF-Thr-NH₂ (23), and des-AA^{1,2,4−6,10,12,13}-[DAgl(NMe,2naphthoyl)⁸,IAmp⁹,Tyr¹¹]-SRIF-NH₂ (27) in DMSO. Though the analogues have the sst₁ pharmacophore residues at the previously determined distances from each other, the positioning of the aromatic residues in 16, 23, and 27 is different from that described earlier, suggesting an induced fit mechanism for sst₁ binding of these novel, less constrained sst₁-selective family members.