Structural and conformational modifications of α-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities

Michael D. Hirsch, Thomas L. O'Donohue, Ruth Wilson, Tomi K. Sawyer, Victor J. Hruby, Mac E. Hadley, Wayne L. Cody, James J. Knittel, Jacqueline Crawley

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1197-1201
Number of pages5
JournalPeptides
Volume5
Issue number6
DOIs
StatePublished - 1984
Externally publishedYes

Fingerprint

Melanocyte-Stimulating Hormones
Grooming
Peptides
Cyclization
Structure-Activity Relationship
Bioactivity
Bioassay
Melanocytes
Biological Assay
Anura
Adrenocorticotropic Hormone
Rats
Elongation
Assays
Skin
Injections

Keywords

  • Behavior
  • Bioactivity
  • Brain
  • Conformation
  • Grooming
  • Neuropeptide
  • Structure-activity
  • α-MSH/ACTH

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

Structural and conformational modifications of α-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities. / Hirsch, Michael D.; O'Donohue, Thomas L.; Wilson, Ruth; Sawyer, Tomi K.; Hruby, Victor J.; Hadley, Mac E.; Cody, Wayne L.; Knittel, James J.; Crawley, Jacqueline.

In: Peptides, Vol. 5, No. 6, 1984, p. 1197-1201.

Research output: Contribution to journalArticle

Hirsch, MD, O'Donohue, TL, Wilson, R, Sawyer, TK, Hruby, VJ, Hadley, ME, Cody, WL, Knittel, JJ & Crawley, J 1984, 'Structural and conformational modifications of α-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities', Peptides, vol. 5, no. 6, pp. 1197-1201. https://doi.org/10.1016/0196-9781(84)90187-6
Hirsch, Michael D. ; O'Donohue, Thomas L. ; Wilson, Ruth ; Sawyer, Tomi K. ; Hruby, Victor J. ; Hadley, Mac E. ; Cody, Wayne L. ; Knittel, James J. ; Crawley, Jacqueline. / Structural and conformational modifications of α-MSH/ACTH4-10 provide melanotropin analogues with highly potent behavioral activities. In: Peptides. 1984 ; Vol. 5, No. 6. pp. 1197-1201.
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AU - Wilson, Ruth

AU - Sawyer, Tomi K.

AU - Hruby, Victor J.

AU - Hadley, Mac E.

AU - Cody, Wayne L.

AU - Knittel, James J.

AU - Crawley, Jacqueline

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AB - 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.

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