Previous studies have identified the (4-10) heptapeptide sequence as the central core of α-MSH/ACTH peptides required for mediation of important biological activities. In the present study, the structure-activity relationships of Nle4-substituted and tsqbCys4, Cys10-bridged cyclic α-MSH analogues, which were previously shown to exhibit a wide range of melanotropic potencies from weak agonism to super potency, were examined for grooming behavioral activity in the rat following intracerebroventricular injections. The results showed that stepwise C-terminal elongation of the linear Nle4-substituted Ac-α-MSH4-10-NH2 increased grooming potencies of the peptides in a manner similar to their actions on melanocytes. The most interesting finding was the observation that cyclization of the inactive linear "central (4-10) core" of α-MSH (Ac-α-MSH4-10) to form Ac-[tsqbCys4, Cys10]-α-MSH4-10-NH2 resulted in a super potent agonist in the grooming assay. However, while cyclization of the (4-10) heptapeptide produced potent agonists on grooming behavior, the structure-activity relationships were different than the frog skin bioassay. These findings support the hypothesis that appropriate structural and confirmational modifications of α-MSH-related peptides can produce profound effects on the bioactivities of the peptides, and suggest that different structural-conformational requirements exist for α-MSH interactions with its various receptors.
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience