THE SYNTHESIS AND BIOLOGICAL EVALUATION OF ALPHA-MELANOTROPIN AND SUBSTANCE P PEPTIDE ANALOGUES (STRUCTURE, FUNCTION).

Persistent Link:
http://hdl.handle.net/10150/187929
Title:
THE SYNTHESIS AND BIOLOGICAL EVALUATION OF ALPHA-MELANOTROPIN AND SUBSTANCE P PEPTIDE ANALOGUES (STRUCTURE, FUNCTION).
Author:
DARMAN, PAUL STEWART.
Issue Date:
1985
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
To investigate the underlying structural features of the neuropeptides α-melanotropin (α-MSH) and substance P (SP), which are responsible for their biological actions, the following study was undertaken. By means of side-chain, fragment and conformational restriction analysis, several α-MSH peptides were prepared by solid-phase synthesis and evaluated by the frog and lizard skin bioassays. Using conformational restriction and fragment methods, several SP peptides were synthesized and examined for biological activity on the guinea-pig isolated ileum, rat brain binding and intrathecal injection assay systems. The results with the new α-MSH analogues show that the histidine-6 side-chain is not needed for signal transduction, but is very important for full potency. The tryptophan-9 side-chain is similarly not needed for signal transduction, but is critically important for full potency. The data also indicate that the positions 6 and 9 side-chains are important for full potency because they likely interact with the melanophore receptor, rather than playing a role in conformationally folding the MSH peptide into a pseudocyclic structure. The results also show that the arginine side-chain at position 8 is not particularly important for signal transduction or full potency, but on the lizard skin bioassay this side-chain is implicated in the previously reported prolongation of Nle⁴, D-Phe⁷-α-MSH. The data provided by the SP peptides suggest that the previously postulated pseudocyclic structure of the 5-11 sequence may not be as fundamental to SP activity as heretofore believed. The data suggest that this type of turn conformation may be important for signal transduction, but is apparently not the only requirement for receptor recognition. Finally, the data show that part of the signal transduction message of SP is contained within the 5-8 region of the peptide, but that most of the receptor recognition elements are probably located outside this sequence.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Neuropeptides.; Substance P.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTHE SYNTHESIS AND BIOLOGICAL EVALUATION OF ALPHA-MELANOTROPIN AND SUBSTANCE P PEPTIDE ANALOGUES (STRUCTURE, FUNCTION).en_US
dc.creatorDARMAN, PAUL STEWART.en_US
dc.contributor.authorDARMAN, PAUL STEWART.en_US
dc.date.issued1985en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractTo investigate the underlying structural features of the neuropeptides α-melanotropin (α-MSH) and substance P (SP), which are responsible for their biological actions, the following study was undertaken. By means of side-chain, fragment and conformational restriction analysis, several α-MSH peptides were prepared by solid-phase synthesis and evaluated by the frog and lizard skin bioassays. Using conformational restriction and fragment methods, several SP peptides were synthesized and examined for biological activity on the guinea-pig isolated ileum, rat brain binding and intrathecal injection assay systems. The results with the new α-MSH analogues show that the histidine-6 side-chain is not needed for signal transduction, but is very important for full potency. The tryptophan-9 side-chain is similarly not needed for signal transduction, but is critically important for full potency. The data also indicate that the positions 6 and 9 side-chains are important for full potency because they likely interact with the melanophore receptor, rather than playing a role in conformationally folding the MSH peptide into a pseudocyclic structure. The results also show that the arginine side-chain at position 8 is not particularly important for signal transduction or full potency, but on the lizard skin bioassay this side-chain is implicated in the previously reported prolongation of Nle⁴, D-Phe⁷-α-MSH. The data provided by the SP peptides suggest that the previously postulated pseudocyclic structure of the 5-11 sequence may not be as fundamental to SP activity as heretofore believed. The data suggest that this type of turn conformation may be important for signal transduction, but is apparently not the only requirement for receptor recognition. Finally, the data show that part of the signal transduction message of SP is contained within the 5-8 region of the peptide, but that most of the receptor recognition elements are probably located outside this sequence.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectNeuropeptides.en_US
dc.subjectSubstance P.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.committeememberBates, Robert B.en_US
dc.contributor.committeememberForster, Leslie R.en_US
dc.contributor.committeememberHadley, Mac E.en_US
dc.contributor.committeememberRupley, John A.en_US
dc.identifier.proquest8512680en_US
dc.identifier.oclc693610237en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.