Novel 3D pharmacophore of alpha-MSH/gamma-MSH hybrids leads to selective human MC1R and MC3R analogues.
To further evaluate elements that could contribute to the 3D topographical structure of gamma-MSH, we have systematically designed a group of linear gamma-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle(3), with l- or d-Phe(6) or d-Nal(2')(6), and with d-Trp(8) or d-Nal(2')(8). It was found that changing the C-terminal acid in gamma-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp(8) with d-Nal(2')(8) and Phe(6) with d-Phe(6) in gamma-MSH-NH(2) forms a selective antagonist for the hMC3R, whereas, substitution of Phe(6) with d-Nal(2')(6) and replacing Trp(8) with d-Trp(8) at gamma-MSH-NH(2) yields a selective partial agonist for the hMC1R. Finally, substitution of His(5) with Pro(5) and Trp(8) with d-Nal(2')(8) in gamma-MSH-NH(2) leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle(3)-gamma-MSH-NH(2), there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand-receptor interaction for gamma-MSH analogues that may explain the enhanced binding affinities of the Nle(3)-gamma-MSH-NH(2) analogues. Our results indicate that increasing the hydrophobicity and replacing Phe(6) and Trp(8) with bulkier aromatic amino acid residues is very important for selectivity of alpha-MSH/gamma-MSH hybrids for hMCRs.
Cai
Minying
M
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
Mayorov
Alexander V
AV
Cabello
Christopher
C
Stankova
Magda
M
Trivedi
Dev
D
Hruby
Victor J
VJ
D000262:Adenylyl Cyclases / Q000096:biosynthesis; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D013058:Mass Spectrometry; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D011979:Receptors, Pituitary Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000737:chemistry* / Q000494:pharmacology; D019825:gamma-MSH / Q000737:chemistry* / Q000494:pharmacology
D008024:Ligands; D011979:Receptors, Pituitary Hormone; D019825:gamma-MSH; D000521:alpha-MSH; C029446:MSH receptor; D000262:Adenylyl Cyclases