Cyclic analogs of α-melanocyte-stimulating hormone (αMSH) with high agonist potency and selectivity at human melanocortin receptor 1b

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• 作者：Maria A. Bednarek ; Tanya MacNeil ; Rui Tang ; Tung M. Fong ; M. Angeles Cabello ; Marta Maroto ; Ana Teran
• 关键词：Melanocortin ; Melanocortin receptor ; Agonist ; Human melanocortin receptor 1 ; hMC1R ; Binding affinity ; cAMP accumulation assay ; MTII
• 刊名：Peptides
• 出版年：2008
• 期刊代码：59_01969781
• 类别：neu
• 出版时间：June 2008
• 卷：29
• 期：6
• 页码：1010-1017
• 文件大小：229 K

摘要

http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">-Melanotropin (http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">MSH), Ac-Ser¹-Tyr²-Ser³-Met⁴-Glu⁵-His⁶-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂,href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0M-4RW432S-3&_user=10&_coverDate=06%2F30%2F2008&_rdoc=18&_fmt=full&_orig=browse&_srch=doc-info(%23toc%234866%232008%23999709993%23688979%23FLA%23display%23Volume)&_cdi=4866&_sort=d&_docanchor=&_ct=26&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=b8ce518efe90887d6f9459ce6c8267c3#fn1">¹ has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of http://www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">MSH were studied. These ligands were analogs of MTII, Ac-Nle⁴-cyclo-(Asp⁵-His⁶-d-Phe⁷-Arg⁸-Trp⁹-Lys¹⁰)-NH₂, a potent pan-agonist at the human melanocortin receptors (hMC1,3–5R). In the structure of MTII, the His⁶-D-Phe⁷-Arg⁸-Trp⁹ segment has been recognized as “essential” for molecular recognition at the human melanocortin receptors (hMC1,3–5R). Herein, the role of the Trp⁹ in the ligand interactions with the hMC1b,3–5R has been reevaluated. Analogs with various amino acids in place of Trp⁹ were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3–5R). Several of the new peptides were high potency agonists (partial) at hMC1bR (EC₅₀ from 0.5 to 20 nM) and largely inactive at hMC3–5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.