Mayorov Alexander V, Cai Minying, Palmer Erin S, Dedek Matthew M, Cain James P, Van Scoy April R, Tan Bahar, Vagner Josef, Trivedi Dev, Hruby Victor J
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 2008 Jan 24;51(2):187-95. doi: 10.1021/jm070461w. Epub 2007 Dec 19.
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.
在环内酰胺α-黑素细胞刺激激素（α-MSH）衍生的Pro(6)-D-Phe(7)/D-Nal(2')(7)-Arg(8)-Trp(9)-Lys(10)-NH2五肽模板的Pro(6)的α-氨基与Lys(10)的氨基之间引入的多种二羧酸连接体，产生了纳摩尔范围的选择性人黑素皮质素3型受体（hMC3R）激动剂和拮抗剂。用2,3-吡嗪二甲酸取代Pro(6)残基和二羧酸连接体，得到了一种高选择性的纳摩尔范围的hMC3R部分激动剂（类似物12，c[CO-2,3-吡嗪-CO-D-Phe-Arg-Trp-Lys]-NH2，半数有效浓度（EC50）=27 nM，最大环磷酸腺苷（cAMP）的70%）和一种hMC3R拮抗剂（类似物13，c[CO-2,3-吡嗪-CO-D-Nal(2')-Arg-Trp-Lys]-NH2，半数抑制浓度（IC50）=23 nM）。建模实验表明，2,3-吡嗪二甲酸与D-Phe/D-Nal(2')残基稳定了一种类似β-转角的结构，这解释了相应肽的高效能。在第6位放置一个正亮氨酸（Nle）残基产生了一种hMC3R/hMC5R拮抗剂（类似物15，c[CO-(CH 2)2-CO-Nle-D-Nal(2')-Arg-Trp-Lys]-NH2，IC50分别为12和17 nM），类似于先前描述的环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将作为关键的生化工具，用于阐明生理上重要的黑素皮质素-3受体所执行的全部功能谱。
