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The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands

The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the...

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Autores principales: Ericson, Mark D., Freeman, Katie T., LaVoi, Travis M., Donow, Haley M., Santos, Radleigh G., Giulianotti, Marc A., Pinilla, Clemencia, Houghten, Richard A., Haskell-Luevano, Carrie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299128/
https://www.ncbi.nlm.nih.gov/pubmed/37373293
http://dx.doi.org/10.3390/ijms241210145
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author Ericson, Mark D.
Freeman, Katie T.
LaVoi, Travis M.
Donow, Haley M.
Santos, Radleigh G.
Giulianotti, Marc A.
Pinilla, Clemencia
Houghten, Richard A.
Haskell-Luevano, Carrie
author_facet Ericson, Mark D.
Freeman, Katie T.
LaVoi, Travis M.
Donow, Haley M.
Santos, Radleigh G.
Giulianotti, Marc A.
Pinilla, Clemencia
Houghten, Richard A.
Haskell-Luevano, Carrie
author_sort Ericson, Mark D.
collection PubMed
description The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1–R5) were subjected to parallel structure–activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds.
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spelling pubmed-102991282023-06-28 The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands Ericson, Mark D. Freeman, Katie T. LaVoi, Travis M. Donow, Haley M. Santos, Radleigh G. Giulianotti, Marc A. Pinilla, Clemencia Houghten, Richard A. Haskell-Luevano, Carrie Int J Mol Sci Article The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1–R5) were subjected to parallel structure–activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R. The R2, R3, and R5 positions were required for full MC3R efficacy, while truncation of either the R1 or R4 positions in all three compounds resulted in full MC3R agonists. Two additional fragments, featuring molecular weights below 300 Da, were also identified that possessed full agonist efficacy and micromolar potencies at the mMC5R. These SAR experiments may be useful in generating new small-molecule ligands and chemical probes for the melanocortin receptors to help elucidate their roles in vivo and as therapeutic lead compounds. MDPI 2023-06-14 /pmc/articles/PMC10299128/ /pubmed/37373293 http://dx.doi.org/10.3390/ijms241210145 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ericson, Mark D.
Freeman, Katie T.
LaVoi, Travis M.
Donow, Haley M.
Santos, Radleigh G.
Giulianotti, Marc A.
Pinilla, Clemencia
Houghten, Richard A.
Haskell-Luevano, Carrie
The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title_full The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title_fullStr The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title_full_unstemmed The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title_short The Parallel Structure–Activity Relationship Screening of Three Compounds Identifies the Common Agonist Pharmacophore of Pyrrolidine Bis-Cyclic Guanidine Melanocortin-3 Receptor (MC3R) Small-Molecule Ligands
title_sort parallel structure–activity relationship screening of three compounds identifies the common agonist pharmacophore of pyrrolidine bis-cyclic guanidine melanocortin-3 receptor (mc3r) small-molecule ligands
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299128/
https://www.ncbi.nlm.nih.gov/pubmed/37373293
http://dx.doi.org/10.3390/ijms241210145
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