Collect. Czech. Chem. Commun. 1984, 49, 2680-2688

Modification of the disulfide bridge in cyclic melanotropins

Michal Lebla, Wayne L. Codya, Brian C. Wilkesa, Victor J. Hrubya, Anna M. de L. Castruccib and Mac E. Hadleyb

a University of Arizona, Department of Chemistry, Tucson, AZ 85721, U.S.A.
b University of Arizona, Department of Anatomy and Molecular and Cellular Biology, Tucson, AZ 85721, U.S.A.


We have prepared a cyclic analog containing a thiomethylene bridge in place of the disulfide bridge in order to further analyze the importance of a cyclic structure for the biological activity of α-MSH (α-melanotropin, α-melanocyte stimulating hormone) and to determine if the biological activity of [Cys4, Cys10]-α-MSH is related to disulfide interchange. The carba analog was based on the highly potent Ac-[Cys4, Cys10]-α-MSH4-13-NH2 fragment analog in which cysteine in residue 4 was replaced by 3-mercaptopropanoic acid (Mpa). This carba analog was slightly less active than the disulfide bridged compound in both in vitro bioassay systems tested (frog and lizard skin systems). Oxidation of the carba analog to the sulfoxide led to a moderate loss of activity in both assays. We also reduced the 4-13 disulfide-containing compound [Mpa4, Cys10]-α-MSH4-13-NH2 and examined the reduced analog for melanotropic activity. It was found that opening of the disulfide led to a large loss of potency. The bis-sulfhydryl compound may have been non-specifically bound to, and/ or internalized inside the tissue, but did not show any inhibitory activity.