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Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor

A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH(2) (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG bin...

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Autores principales: Bhagwanth, Swapna, Mishra, Ram K, Johnson, Rodney L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566759/
https://www.ncbi.nlm.nih.gov/pubmed/23400263
http://dx.doi.org/10.3762/bjoc.9.24
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author Bhagwanth, Swapna
Mishra, Ram K
Johnson, Rodney L
author_facet Bhagwanth, Swapna
Mishra, Ram K
Johnson, Rodney L
author_sort Bhagwanth, Swapna
collection PubMed
description A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH(2) (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG binds to the D(2) dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH(2) pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold. This information was used to transform existing positive modulators into negative modulators, which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics.
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spelling pubmed-35667592013-02-11 Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor Bhagwanth, Swapna Mishra, Ram K Johnson, Rodney L Beilstein J Org Chem Review A variety of stable, small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro-Leu-Gly-NH(2) (PLG) modulates dopaminergic neurotransmission. Photoaffinity labeling ligands based upon PLG peptidomimetics have been used to establish that PLG binds to the D(2) dopamine receptor at a site that is different from the orthosteric site, thus making PLG and its peptidomimetics allosteric modulators of the dopamine receptor. Through the design, synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam, bicyclic, and spiro-bicyclic scaffolds, support was provided for the hypothesis that the bioactive conformation of PLG is a type II β-turn. In addition, studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH(2) pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold. This information was used to transform existing positive modulators into negative modulators, which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of PLG peptidomimetics. Beilstein-Institut 2013-01-30 /pmc/articles/PMC3566759/ /pubmed/23400263 http://dx.doi.org/10.3762/bjoc.9.24 Text en Copyright © 2013, Bhagwanth et al. https://creativecommons.org/licenses/by/2.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms)
spellingShingle Review
Bhagwanth, Swapna
Mishra, Ram K
Johnson, Rodney L
Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title_full Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title_fullStr Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title_full_unstemmed Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title_short Development of peptidomimetic ligands of Pro-Leu-Gly-NH(2) as allosteric modulators of the dopamine D(2) receptor
title_sort development of peptidomimetic ligands of pro-leu-gly-nh(2) as allosteric modulators of the dopamine d(2) receptor
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566759/
https://www.ncbi.nlm.nih.gov/pubmed/23400263
http://dx.doi.org/10.3762/bjoc.9.24
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