Collect. Czech. Chem. Commun. 1988, 53, 2549-2573

Conformational and biological analysis of α-MSH fragment analogues with sterically constrained amino acid residues

Victor J. Hrubya, Wayne L. Codya, Ana Maria de Lauro Castruccib and Mac E. Hadleyb

a Department of Chemistry, University of Arizona, Tucson, Arizona 85721, U.S.A.
b Department of Anatomy, University of Arizona, Tucson, Arizona 85724, U.S.A.


Conformational and biological analysis of the linear 4-11 fragment analogues, Ac-[Nle4]-α-MSH4-11-NH2 (II) and Ac-[Nle4, D-Phe7]-α-MSH4-11-NH2 (III) and related analogues have been undertaken. In solution, the peptide backbone is flexible, but in the case of D-Phe7 analogues an interaction of the His6, D-Phe7 and Arg8 amino acid side chain groups may be present based on the shielding patterns observed in the proton NMR and on comparison of NT1 values. The importance of the position 7 to the biological and conformational properties was further examined by substitution of either L- or D-phenylglycine (Pgl) or L- and D-1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) for phenylalanine-7. Ac-[Nle4, Pgl7]-α-MSH4-11-NH2 (IV), Ac-[Nle4, D-Pgl7]-α-MSH4-11-NH2 (V), Ac-[Nle4, Tic7]-α-MSH4-11-NH2 (VI), and Ac-[Nle4, D-Tic7]-α-MSH4-11-NH2 (VII) were prepared. These substituted analogues were examined for their biological activities and conformational properties with emphasis on the three-dimensional orientation of the aromatic ring in the position 7, and the effects of the aromatic ring on adjacent amino acids, and on biological activities. The relative potencies of the analogues in the frog skin assay system were: II (1·00); III (118); IV (82·4); V (0·18); VI (0·18); and VII (0·14); and in the lizard skin bioassay they were: II (1·00); III (10·0); IV (0·14); V (0·005); VI (0·00025); and VII (0·01). On the basis of the NMR studies the L-phenylglycine substitution results in an enhanced ring stacking interaction between the phenyl ring of Pgl7 and the indole ring of Trp9. The 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) substitution leads to significant backbone restriction and an interaction of the alpha proton of His6 with the carbonyl of Glu5. The possible relationships of these effects to biological activity are discussed.