Structural and conformational modifications of alpha-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities |
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Authors: | M D Hirsch T L O'Donohue R Wilson T K Sawyer V J Hruby M E Hadley W L Cody J J Knittel J N Crawley |
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Institution: | 1. Experimental Therapuetics Branch, NINCDS, NIH USA;2. Department of Chemistry, University of Arizona, Tucson, AZ 85721 USA;3. Department of Molecular and Cellular Biology and Anatomy, University of Arizona, Tucson, AZ 85721 USA;4. Clinical Neuroscience Branch, NIMH, NIH USA |
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Abstract: | Previous studies have identified the (4-10) heptapeptide sequence as the central core of alpha-MSH/ACTH peptides required for mediation of important biological activities. In the present study, the structure-activity relationships of Nle4-substituted and Cys4,Cys10-bridged cyclic alpha-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-alpha-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 alpha-MSH (Ac-alpha-MSH4-10) to form Ac-Cys4,Cys10]-alpha-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 alpha-MSH-related peptides can produce profound effects on the bioactivities of the peptides, and suggest that different structural-conformational requirements exist for alpha-MSH interactions with its various receptors. |
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Keywords: | Neuropeptide Conformation Structure-activity Bioactivity Brain Behavior Grooming |
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