Results of energy calculations for a-MSH (a-melanocyte stimulating hormone, Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 ) and [D-Phe 7 ]a-MSH were used for design of cyclic peptides with the general aim to stabilize different conformational isomers of the parent compound. The minimal structural modifications of the conformationally flexible Gly 10 residue, as substitutions for L-Ala, D-Ala, or Aib (replacing of hydrogen atoms by methyl groups), were applied to obtain octa-and heptapeptide analogues of a-MSH(4-11) and a-MSH(5-11), which were cyclized by lactam bridges between the side chains in positions 5 and 11. Some of these analogues, namely those with substitutions of the Gly 10 residue with L-Ala or Aib, showed biological activity potencies on frog skin comparable to the potency of the parent tridecapeptide hormone. Additional energy calculations for designed cyclic analogues were used for further refinement of the model for the biologically active conformations of the His-Phe-Arg-Trp ''message'' sequence within the sequences of a-MSH and [D-Phe 7 ]a-MSH. In such conformations the aromatic moieties of the side chains of the His 6 , L /D-Phe 7 , and Trp 9 residues form a continuous hydrophobic ''surface,'' presumably interacting with a complementary receptor site. This feature is characteristic for low-energy conformers of active cyclic analogues, but it is absent in the case of inactive analogues. This particular spatial arrangement of functional groups involved in the message sequence is very close for a-MSH and [D-Phe 7 ]a-MSH, as well as for biologically active cyclic analogues despite differences of dihedral angle values for corresponding low-energy conformations.