α-黑素细胞刺激激素 (α-MSH) 的环状内酰胺类似物靶向人黑皮质素-3 受体的结构-活性关系。,Journal of Medicinal Chemistry

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α-黑素细胞刺激激素 (α-MSH) 的环状内酰胺类似物靶向人黑皮质素-3 受体的结构-活性关系。
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2008 Jan 24 , DOI: 10.1021/jm070461w
Alexander V Mayorov ₁ , Minying Cai , Erin S Palmer , Matthew M Dedek , James P Cain , April R Van Scoy , Bahar Tan , Josef Vagner , Dev Trivedi , Victor J Hruby

Affiliation

在环状内酰胺 α-黑素细胞刺激激素 (α-MSH) 衍生的 Pro(6) 的 Pro(6) 的 α-氨基和 Lys(10) 的 α-氨基之间引入多种二羧酸连接基 - D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 五肽模板可产生纳摩尔范围的选择性 hMC3R 激动剂和拮抗剂。用 2,3-吡嗪-二羧酸替换 Pro(6) 残基和二羧酸连接体提供了高选择性纳摩尔范围的 hMC3R 部分激动剂（类似物 12，c[CO-2,3-吡嗪-CO-D-Phe] -Arg-Trp-Lys]-NH2，EC50 = 27 nM，最大 cAMP 70%）和 hMC3R 拮抗剂（类似物 13，c[CO-2,3-吡嗪-CO-D-Nal(2')-Arg- Trp-Lys]-NH2，IC50 = 23 nM）。建模实验表明，2,3-吡嗪二甲酸可通过 D-Phe/D-Nal(2') 残基稳定 β 转角样结构，这解释了相应肽的高效能。将 Nle 残基置于位置 6 产生 hMC3R/hMC5R 拮抗剂（类似物 15，c[CO-(CH 2)2-CO-Nle-D-Nal(2')-Arg-Trp-Lys]-NH2，IC50 = 12 和 17 nM，分别），类似于先前描述的环状 γ-黑素细胞刺激激素（γ-MSH）衍生的 hMC3R/hMC5R 拮抗剂。这些新开发的促黑素细胞将作为关键的生化工具，用于阐明生理上重要的黑皮质素-3 受体所发挥的全部功能。

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Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.

A variety of dicarboxylic acid linkers introduced between the alpha-amino group of Pro(6) and the -amino group of Lys(10) of the cyclic lactam alpha-melanocyte-stimulating hormone (alpha-MSH)-derived Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro(6) residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a beta-turn-like structure with the D-Phe/D-Nal(2') residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH 2)2-CO-Nle-D-Nal(2')-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic gamma-melanocyte-stimulating hormone (gamma-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.

更新日期：2017-01-31

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