Substitution of the Side-Chain-Constrained Amino Acids β-Methyl-2‘,6‘-Dimethyl-4‘-Methoxytyrosine in Position 2 of a Bicyclic Oxytocin Analogue Provides Unique Insights into the Bioactive Topography of Oxytocin Antagonists

Liao, Shiyong; Shenderovich, Mark D.; Zhang, Zhigang; Maletı́nská, Lenka; Slaninová, Jiřina; Hruby, Victor J.

doi:10.1021/ja980848b

Cited by 25 publications

(13 citation statements)

References 23 publications

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“…β ‐Substituted isomers of the same amino acid have similar physical and chemical properties, such as electronegativity and hydrophobicity, but their side chain conformations are differentially biased by nonbonding or other interactions between vicinal substituents. Hruby et al have successfully developed all four isomers of topographically constrained β ‐methyl‐2′,6′‐dimethyltyrosines (TMT) and by introducing them into DPDPE obtained a single isomer that was very potent and highly selective for the δ ‐opioid receptor (31–33,39–44), thus demonstrating the great significance of chi space in peptide ligand–protein interactions. In order to obtain selective and potent agonists and antagonists for melanocortin receptors, we have synthesized several MT‐II (25,26) analogs by substituting His 6 and d ‐Phe 7 with β ‐modified prolines.…”

Section: Introductionmentioning

confidence: 99%

Biological and conformational study of β‐substituted prolines in MT‐II template: steric effects leading to human MC5 receptor selectivity*

Cai

Mayorov

et al. 2004

The Journal of Peptide Research

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To investigate the molecular basis for the interaction of the chi-constrained conformation of melanotropin peptide with the human melanocortin receptors, a series of beta-substituted proline analogs were synthesized and incorporated into the Ac-Nle-C[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 (MT-II) template at the His6 and D-Phe7 positions. It was found that the binding affinities generally diminished as the steric bulk of the p-substituents of the 3-phenylproline residues increased. From (2S, 3R)-3-phenyl-Pro6 to (2S, 3R)-3-(p-methoxyphenyl)-Pro6 analogs the binding affinity decreased 23-fold at the human melanocortin-3 receptor (hMC3R), 17-fold at the hMC4R, and eight-fold at the hMC5R, but selectivity for the hMC5R increased. In addition, the substitution of the D-Phe7 residue with a (2R, 3S)-3-phenyl-Pro resulted in greatly reduced binding affinity (10(3)-10(5)) at these melanocortin receptors. Macromodel's Large Scale Low Mode (LLMOD) with OPLS-AA force field simulations revealed that both MT-II and SHU-9119 share a similar backbone conformation and topography with the exception of the orientation of the side chains of D-Phe7/D-Nal (2')7 in chi space. Introduction of the dihedrally constrained phenylproline analogs into the His6 position (analogs 2-6) caused topographical changes that might be responsible for the lower binding affinities. Our findings indicate that hMC3 and hMC4 receptors are more sensitive to steric effects and conformational constraints than the hMC5 receptor. This is the first example for melanocortin receptor selectivity where the propensity of steric interactions in chi space of beta-modified Pro6 analogs of MT-II has been shown to play a critical role for binding as well as bioefficacy of melanotropins at hMC3 and hMC4 receptors, but not at the hMC5 receptor.

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Section: Introductionmentioning

confidence: 99%

Biological and conformational study of β‐substituted prolines in MT‐II template: steric effects leading to human MC5 receptor selectivity*

Cai

Mayorov

et al. 2004

The Journal of Peptide Research

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“…Efforts to eliminate these toxicities have not been successful. When similar conformational constraints in χ space for the Tyr 2 position of oxytocin (H-c[Cys-Try-Ile-Gln-Asn-Cys]-Pro-Leu-Gly-NH 2 ) were made along with the p-methoxy-Tyr analog, potent analogs with superior properties and unique structural features were obtained (50). …”

Section: Design Of Nonpeptide Ligands For a Receptor From A Peptide Nmentioning

confidence: 99%

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

Hruby

Cai

2013

Annu. Rev. Pharmacol. Toxicol.

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Peptide hormones and neurotransmitters are of central importance in most aspects of intercellular communication and are involved in virtually all degenerative diseases. In this review, we discuss physicochemical approaches to the design of novel peptide and peptidomimetic agonists, antagonists, inverse agonists, and related compounds that have unique biological activity profiles, reduced toxic side effects, and, if desired, the ability to cross the blood-brain barrier. Designing ligands for specific biological and medical needs is emphasized, as is the close collaboration of chemists and biologists to maximize the chances for success. Special emphasis is placed on the use of conformational (φ-ψ space) and topographical (χ space) considerations in design.

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“…In yet another example of the use of the χ -constrained amino acid TMT, incorporation of the four isomers of the O -methoxy derivative of TMT in oxytocin107 provided unique new insights into the bioactive topography of oxytocin antagonists.…”

Section: Use Of χ (χ) Space To Develop An Inverse Agonistmentioning

confidence: 99%

Organic Chemistry and Biology: Chemical Biology Through the Eyes of Collaboration

Hruby

2009

J. Org. Chem.

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From a scientific perspective, efforts to understand biology including what constitutes health and disease has become a chemical problem. However, chemists and biologists "see" the problems of understanding biology from different perspectives, and this has retarded progress in solving the problems especially as they relate to health and disease. This suggests that close collaboration between chemists and biologists is not only necessary but essential for progress in both the biology and chemistry that will provide solutions to the global questions of biology. This perspective has directed my scientific efforts for the past 45 years, and in this overview I provide my perspective of how the applications of synthetic chemistry, structural design, and numerous other chemical principles have intersected in my collaborations with biologists to provide new tools, new science, and new insights that were only made possible and fruitful by these collaborations.In the spring of 1965 I made a fateful decision. I decided to change courses in my scientific career from synthetic chemistry and theoretic organic chemistry and accept an offer to join Vincent du Vigneaud's group at Cornell University Medical College as an Instructor in Biochemistry (I had not taken a course in Biochemistry). In doing so I accepted a challenge he had been working on for many years, the structure of acetone oxytocin (an inactive form of oxytocin which contained 1 mol of acetone and 1 mol of oxytocin) using a combination of synthetic/mechanistic organic chemistry and a relatively new structure tool for solving organic structures (in this case a structure of over 1000 Da), nuclear magnetic resonance spectroscopy. I loved spectroscopy and mechanistic organic chemistry and thought it would be fun to try. It turned out to be a difficult problem, but fortunately we were successful. 1 Thus began my career in what is now called Chemical Biology. Though both of my Professors, A. T. Blomquist, and V. du Vigneaud, were exceptionally supportive and gave me unparalleled freedom in both my Ph.D. and postdoctoral work, respectively, little did I realize the resistance this field would elicit from chemists. However, du Vigneaud, certainly NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the most future-looking scientist I have known, and the father of modern Chemical Biology in peptide and protein chemistry, provided all the incentives I have needed. "Victor, we just keep at it, eventually they will catch on." I also learned that collaboration with biologists and medical doctors, which du Vigneaud had been doing for many years, was essential. This is one of the main reasons I chose The University of Arizona to begin my independent science career: the Medical School is less than a mile from the Chemistry Department. That, and the presence of Carl "Speed" Marvel, one of the giants of organic chemistry and the father of polymer chemistry, who wanted me to come to the University of Arizona and was my strongest advocate.Indeed, I have a...

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Substitution of the Side-Chain-Constrained Amino Acids β-Methyl-2‘,6‘-Dimethyl-4‘-Methoxytyrosine in Position 2 of a Bicyclic Oxytocin Analogue Provides Unique Insights into the Bioactive Topography of Oxytocin Antagonists

Cited by 25 publications

References 23 publications

Biological and conformational study of β‐substituted prolines in MT‐II template: steric effects leading to human MC5 receptor selectivity*

Biological and conformational study of β‐substituted prolines in MT‐II template: steric effects leading to human MC5 receptor selectivity*

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

Organic Chemistry and Biology: Chemical Biology Through the Eyes of Collaboration

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