Cyclic melanotropins: Part VII*: Modified ring structures ‐ synthesis and biological activity

The highly potent cyclic analogue of α‐MSH, Ac‐[Cys⁴, Cys¹⁰]‐α‐MSH_4–13‐NH₂, was structurally modified in position 4. Four analogues were prepared and their biological activities in the in vitro frog and lizard skin bioassays were determined. It was shown that removing the terminal acetylamino group to give [Mpa⁴, Cys¹⁰]‐α‐MSH_4–13‐NH₂ resulted in little change in the biological activity, but a change in the stereochemistry of cysteine in position 4 to give Ac‐[D‐Cys⁴, Cys¹⁰]‐α‐MSH_4–13‐NH₂ led to a small decrease of activity in both bioassays. Decreasing the size of the intramolecular ring by removing one methylene group to give [Maa⁴, Cys¹⁰]‐α‐MSH_4–13‐NH², resulted in an analogue with lower activities in both assays (about 3 times in the lizard and 500 times in the frog), and increasing the size of the ring by one methylene group to give Ac‐[Hcy⁴, Cys¹⁰]‐α‐MSH_4–13‐NH₂ led to much lower activities in the lizard system and similar effects were seen upon decreasing the ring size in the frog skin assay.