(2S,3R)β-Methyl-2′,6′-dimethyltyrosine-l-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-l-Tic-OH] Is a Potent, Selective δ-Opioid Receptor Antagonist in Mouse Brain

Hosohata, Keiko; Varga, Éva; Alfaro-Lopez, Josue; Tang, Xuejun; Vanderah, Todd W.; Porreca, Frank; Hruby, Victor J.; Roeske, William R.; Yamamura, Henry I.

doi:10.1124/jpet.102.042929

Cited by 10 publications

(3 citation statements)

References 26 publications

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“…The dipeptide had weak and partial agonist activity in the guinea pig ileum (OPRM1) assay (Table 2). Further extensive studies demonstrated that [2 S ,3 R ]TMT-L-Tic-OH was a potent inverse agonist at the hOPRD1 (44) and a potent and selective OPRD1 neutral antagonist in the mouse brain (45). These comprehensive studies demonstrate several important insights that could be obtained using topographical constraints in addition to those of enhanced potency and receptor selectivity already discussed:

The topographical requirements of the tyrosine pharmacophore moiety for agonist and antagonist activity of opioid peptides at the OPRD1 are similar.

…”

Section: Development Of δ Opioid Receptor Antagonists: Topographical mentioning

confidence: 99%

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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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The topographical requirements of the tyrosine pharmacophore moiety for agonist and antagonist activity of opioid peptides at the OPRD1 are similar.

…”

Section: Development Of δ Opioid Receptor Antagonists: Topographical mentioning

confidence: 99%

“… a Data from Reference 43. b Data from Reference 45. Abbreviations: DAMGO, [D-Ala 2 , N -MePhe 4 ,Gly-ol]enkephalin; DPDPE, c[D-Pen 2 ,D-Pen 5 ]enkephalin; GPI, guinea pig ileum; MVD, mouse vas deferens; ND, not determined; TMT, β-methyl-2′,6′-dimethyltyrosine (trimethyltyrosine). …”

Section: Figurementioning

confidence: 99%

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

Hruby

Cai

2013

Annu. Rev. Pharmacol. Toxicol.

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“…In this case, both the (2 S ,3 R )-TMT-Tic-OH (IC 50 = 9.3 nM) and the (2 S ,3 S )-TMT-Tic-OH (IC 50 = 124 nM) ligands were found to be potent δ-opioid receptor antagonists in the MVD assay. The most exciting results, however, came when we examined G-protein activation using the GTPγS assay with membranes from δ receptor transfected cell lines and found that the (2 S ,3 R )-TMT-Tic-OH analogue was an inverse agonist at human δ opioid receptor . Inverse agonists are powerful potential drugs when one encounters constituitively active receptors in biological systems…”

Section: A Few Principles In Chemical Biologymentioning

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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Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

Mollica

Stefanucci

Costante

et al. 2015

Studies in Natural Products Chemistry

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(2S,3R)β-Methyl-2′,6′-dimethyltyrosine-l-tetrahydroisoquinoline-3-carboxylic acid [(2S,3R)TMT-l-Tic-OH] Is a Potent, Selective δ-Opioid Receptor Antagonist in Mouse Brain

Cited by 10 publications

References 26 publications

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

Design of Peptide and Peptidomimetic Ligands with Novel Pharmacological Activity Profiles

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

Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides

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