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Agonist Potency

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Maria A Bednarek – 1st expert on this subject based on the ideXlab platform

  • cyclic analogs of α melanocyte stimulating hormone αmsh with high Agonist Potency and selectivity at human melanocortin receptor 1b
    Peptides, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    Abstract α-Melanotropin (αMSH), Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 , 1 has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of αMSH were studied. These ligands were analogs of MTII, Ac-Nle 4 -cyclo-(Asp 5 -His 6 – d -Phe 7 -Arg 8 -Trp 9 -Lys 10 )-NH 2 , a potent pan-Agonist at the human melanocortin receptors (hMC1,3–5R). In the structure of MTII, the His 6 -D-Phe 7 -Arg 8 -Trp 9 segment has been recognized as “essential” for molecular recognition at the human melanocortin receptors (hMC1,3–5R). Herein, the role of the Trp 9 in the ligand interactions with the hMC1b,3–5R has been reevaluated. Analogs with various amino acids in place of Trp 9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3–5R). Several of the new peptides were high Potency Agonists (partial) at hMC1bR (EC 50 from 0.5 to 20 nM) and largely inactive at hMC3–5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.

  • analogs of α melanocyte stimulating hormone with high Agonist Potency and selectivity at human melanocortin receptor 1b the role of trp9 in molecular recognition
    Biopolymers, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    α-Melanocyte stimulating hormone (αMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, is an endogenous Agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with αMSH and its synthetic analog NDP-αMSH, Ac-Ser1-Tyr2-Ser3-Nle4-Glu5-His6-D-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, have been previously proposed. In those models, the 6–9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp9 of NDP-αMSH in interactions with hMC1bR. Analogs of NDP-αMSH with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high Agonist Potency at hMC1bR (EC50 = 0.5–5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp9 residue of NDP-αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008.

    This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

  • Analogs of MTII, Lactam Derivatives of α-Melanotropin, Modified at the N-Terminus, and Their Selectivity at Human Melanocortin Receptors 3, 4, and 5
    Biochemical and Biophysical Research Communications, 1999
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Rubana N. Kalyani, Lex H.t. Van Der Ploeg, David H. Weinberg

    Abstract:

    Abstract In search for selective Agonists at human melanocortin-4 receptor, proline-substituted analogs of MTII, a potent nonselective Agonist at melanocortin receptors, were prepared by solid-phase syntheses and evaluated for their ability to bind and activate human MC-3, MC-4, and MC-5 receptors. Replacement of Nle 4 with Pro resulted in [Pro 4 ]MTII with affinity to and Agonist Potency at hMC-4R similar to MTII, but with about 400-fold lower Potency at hMC-5R and about 20-fold lower Potency at hMC-3R. The substantial increase in selectivity of [Pro 4 ]MTII with respect to hMC-5R prompted us to investigate additional analogs of MTII with modified N-termini. The Ac-Nle 4 segment, not encompassed in the lactam ring, was substituted with flexible, hydrophobic, or hydrophilic substituents, and also, with residues resembling proline. The similar Agonist Potency of these peptides to that of MTII at hMC-4R but significantly lower activity of these compounds at hMC-5R demonstrated that the N-terminal fragment of MTII has virtually no effect on the binding affinity and activation at hMC-4R, but it is essential for full Potency at hMC-5R.

Ana Teran – 2nd expert on this subject based on the ideXlab platform

  • cyclic analogs of α melanocyte stimulating hormone αmsh with high Agonist Potency and selectivity at human melanocortin receptor 1b
    Peptides, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    Abstract α-Melanotropin (αMSH), Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 , 1 has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of αMSH were studied. These ligands were analogs of MTII, Ac-Nle 4 -cyclo-(Asp 5 -His 6 – d -Phe 7 -Arg 8 -Trp 9 -Lys 10 )-NH 2 , a potent pan-Agonist at the human melanocortin receptors (hMC1,3–5R). In the structure of MTII, the His 6 -D-Phe 7 -Arg 8 -Trp 9 segment has been recognized as “essential” for molecular recognition at the human melanocortin receptors (hMC1,3–5R). Herein, the role of the Trp 9 in the ligand interactions with the hMC1b,3–5R has been reevaluated. Analogs with various amino acids in place of Trp 9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3–5R). Several of the new peptides were high Potency Agonists (partial) at hMC1bR (EC 50 from 0.5 to 20 nM) and largely inactive at hMC3–5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.

  • analogs of α melanocyte stimulating hormone with high Agonist Potency and selectivity at human melanocortin receptor 1b the role of trp9 in molecular recognition
    Biopolymers, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    α-Melanocyte stimulating hormone (αMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, is an endogenous Agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with αMSH and its synthetic analog NDP-αMSH, Ac-Ser1-Tyr2-Ser3-Nle4-Glu5-His6-D-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, have been previously proposed. In those models, the 6–9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp9 of NDP-αMSH in interactions with hMC1bR. Analogs of NDP-αMSH with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high Agonist Potency at hMC1bR (EC50 = 0.5–5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp9 residue of NDP-αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008.

    This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Tanya Macneil – 3rd expert on this subject based on the ideXlab platform

  • cyclic analogs of α melanocyte stimulating hormone αmsh with high Agonist Potency and selectivity at human melanocortin receptor 1b
    Peptides, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    Abstract α-Melanotropin (αMSH), Ac-Ser 1 -Tyr 2 -Ser 3 -Met 4 -Glu 5 -His 6 -Phe 7 -Arg 8 -Trp 9 -Gly 10 -Lys 11 -Pro 12 -Val 13 -NH 2 , 1 has been long recognized as an important physiological regulator of skin and hair pigmentation in mammals. Binding of this peptide to the melanocortin receptor 1 (MC1R) leads to activation of tyrosinase, the key enzyme of the melanin biosynthesis pathway. In this study, interactions of the human MC1bR (an isoform of the receptor 1a) with the synthetic cyclic analogs of αMSH were studied. These ligands were analogs of MTII, Ac-Nle 4 -cyclo-(Asp 5 -His 6 – d -Phe 7 -Arg 8 -Trp 9 -Lys 10 )-NH 2 , a potent pan-Agonist at the human melanocortin receptors (hMC1,3–5R). In the structure of MTII, the His 6 -D-Phe 7 -Arg 8 -Trp 9 segment has been recognized as “essential” for molecular recognition at the human melanocortin receptors (hMC1,3–5R). Herein, the role of the Trp 9 in the ligand interactions with the hMC1b,3–5R has been reevaluated. Analogs with various amino acids in place of Trp 9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4 and 5 (hMC1b,3–5R). Several of the new peptides were high Potency Agonists (partial) at hMC1bR (EC 50 from 0.5 to 20 nM) and largely inactive at hMC3–5R. The bulky aromatic side chain in position 9, such as that in Trp, was found not to be essential to agonism (partial) of the studied peptides at hMC1bR.

  • analogs of α melanocyte stimulating hormone with high Agonist Potency and selectivity at human melanocortin receptor 1b the role of trp9 in molecular recognition
    Biopolymers, 2008
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Tung M Fong, Angeles M Cabello, Marta Maroto, Ana Teran

    Abstract:

    α-Melanocyte stimulating hormone (αMSH), Ac-Ser1-Tyr2-Ser3-Met4-Glu5-His6-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, is an endogenous Agonist for the melanocortin receptor 1 (MC1R), the receptor found in the skin, several types of immune cells, and other peripheral sites. Three-dimensional models of complexes of this receptor with αMSH and its synthetic analog NDP-αMSH, Ac-Ser1-Tyr2-Ser3-Nle4-Glu5-His6-D-Phe7-Arg8-Trp9-Gly10-Lys11-Pro12-Val13-NH2, have been previously proposed. In those models, the 6–9 segment of the ligand was considered essential for the ligand-receptor interactions. In this study, we probed the role of Trp9 of NDP-αMSH in interactions with hMC1bR. Analogs of NDP-αMSH with various amino acids in place of Trp9 were synthesized and tested in vitro in receptor affinity binding and cAMP functional assays at human melanocortin receptors 1b, 3, 4, and 5 (hMC1b,3-5R). Several new compounds displayed high Agonist Potency at hMC1bR (EC50 = 0.5–5 nM) and receptor subtype selectivity greater than 2000-fold versus hMC3-5R. The Trp9 residue of NDP-αMSH was determined to be not essential for molecular recognition at hMC1bR. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 401–408, 2008.

    This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

  • Analogs of MTII, Lactam Derivatives of α-Melanotropin, Modified at the N-Terminus, and Their Selectivity at Human Melanocortin Receptors 3, 4, and 5
    Biochemical and Biophysical Research Communications, 1999
    Co-Authors: Maria A Bednarek, Tanya Macneil, Rui Tang, Rubana N. Kalyani, Lex H.t. Van Der Ploeg, David H. Weinberg

    Abstract:

    Abstract In search for selective Agonists at human melanocortin-4 receptor, proline-substituted analogs of MTII, a potent nonselective Agonist at melanocortin receptors, were prepared by solid-phase syntheses and evaluated for their ability to bind and activate human MC-3, MC-4, and MC-5 receptors. Replacement of Nle 4 with Pro resulted in [Pro 4 ]MTII with affinity to and Agonist Potency at hMC-4R similar to MTII, but with about 400-fold lower Potency at hMC-5R and about 20-fold lower Potency at hMC-3R. The substantial increase in selectivity of [Pro 4 ]MTII with respect to hMC-5R prompted us to investigate additional analogs of MTII with modified N-termini. The Ac-Nle 4 segment, not encompassed in the lactam ring, was substituted with flexible, hydrophobic, or hydrophilic substituents, and also, with residues resembling proline. The similar Agonist Potency of these peptides to that of MTII at hMC-4R but significantly lower activity of these compounds at hMC-5R demonstrated that the N-terminal fragment of MTII has virtually no effect on the binding affinity and activation at hMC-4R, but it is essential for full Potency at hMC-5R.