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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor
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Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor

机译：靶向人类melanocortin-3受体的α-黑素细胞刺激激素（α-MSH）的环状内酰胺类似物的构效关系

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摘要

A variety of dicarboxylic acid linkers introduced between the a-amino group of Pro(6) and the C-ammo group of Lys(10) of the cyclic lactam a-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 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-(CH2)(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.
机译：在Pro（6）的a-氨基和环状内酰胺α-黑素细胞刺激激素（α-MSH）衍生的Pro（6）的Lys（10）的C-ammo基之间引入了各种二羧酸连接基-D-Phe（7）/ D-Nal（2'）（7）-Arg（8）-Trp（9）-Lys（10）-NH2五肽模板导致纳摩尔范围和选择性的hMC3R激动剂和拮抗剂。用2,3-吡嗪-二羧酸取代Pro残基和二羧酸连接基提供了高度选择性的纳摩尔范围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为70％）和hMC3R拮抗剂（类似物13，c [CO-2,3-吡嗪-CO-D-Nal（2'）-Arg-Trp-Lys （-NH 2，IC 50 ＝ 23nM）。建模实验表明，2，3-吡嗪二羧酸稳定了带有D-Phe / D-Nal（2'）残基的β-turn-like结构，这说明了相应肽的高效性。 Nle残基在位置6的位置产生了hMC3R / hMC5R拮抗剂（类似物15，c [CO-（CH2）（2）-CO-Nle-D-Nal（2'）-Arg-Trp-Lys] -NH2， IC50分别为12和17 nM），类似于先前描述的源自环状γ-黑素细胞刺激激素（γ-MSH）的hMC3R / hMC5R拮抗剂。这些新开发的黑素促黑素将作为重要的生化工具，阐明生理上重要的黑黑皮质素-3所发挥的全部功能。受体。

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