Cyclic Melanotropins. 9. 7-D-Phenylalanine Analogues of the Active-Site Sequence

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Abstract
The cyclic melanotropin .**GRAPHIC**. is a highly potent agonist as determined in several melanocyte bioassays. In linear melanotropins, a D-Phe7 substitution leads to increased potency and often prolonged biological activity. In order to determine if this substitution would have the same effect in cyclic melanotropins, a series of these analogs was prepared. The D-Phe7-substituted cyclic melanotropins .**GRAPHIC**. and .**GRAPHIC**. were both more potent than their cyclic L-Phe7-containing counterparts in either the frog or lizard skin bioassay by more than a factor of 10. Neither peptide exhibited prolongation of biological activity in either assay. Substitution of D-Phe7 into the cyclic 4-12 and 4-13 sequences led to a slight or no increase in potency in both assays relative to the L-Phe7 counterparts, but the activity of the melanotropins was ultraprolonged in each assay. .**GRAPHIC**. was about equipotent to .**GRAPHIC**. again demonstrating, as with certain linear and cyclic L-Phe7-containing melanotropins, that the C-terminal amino acid valine is not required for biological activity or for superpotency. Similar to the linear D-Phe7 analogs that possessed ultraprolonged melanotropic activity, the 4-12 and 4-13 cyclic D-Phe7 analogs also displayed the phenomenon of superagonism, which is a time-dependent increase in efficacy over that produced by an equipotent concentration of the native hormone. Cyclization of certain linear melanotropins resulted in analogs with increased resistance to biological degradation by serum enzymes or purified proteolytic enzymes. Incorporation of a D-Phe7 in the cyclic analogs led to melanotropins that were totally resistant to enzymatic inactivation by trypsin.

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