A new approach to receptor ligand design: synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoouinoline carroxylic acid

Wieslaw Kazmierski, Victor J Hruby

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84 Citations (Scopus)

Abstract

Investigations of the physiological functions of opioid receptors (μ,δ,κ and others) require potent and selective receptor ligands. Conformational constraint provides a useful approach to increase receptor selectivity of flexible peptides. This approach reduces the set of low energy conformations accessible for the ligand and thus can provide insight into topologica1 features that may be responsible for high affinity to a particular receptor subtype. Using this approach, we describe a new class of potent and selective μ opioid receptor antagonists and demonstrate a new approach for the design of receptor specific ligands by which a low affinity, "non-physiological" activity of a natural peptide hormone is converted to a high potency, receptor selective ligand for that receptor, and, at the same time, eliminates the activity at the natural receptors for the peptide. Recently we reported the design and synthesis of a new class of μ opioid receptor selective antagonists, of which {A figure is presented}(CTP) was found to be among the most potent and selective, and {A figure is presented}(PCTP) exhibited a sharp decrease of affinity for μ receptors ( 100 foTd) and a modest increase ( 3 fold) in affinity for δ receptors. We now present 1h NMR evidence which suggests a more folded conformation for the latter compound. This result led to the design of further constrained analogues in which a methylene bridge is inserted between the α-amino group and the 2'position of the aromatic ring of n-phe1 in CTP. This analogue {A figure is presented}(TCTP) was found to be the most μ vs. δ receptor selective ligand known (> 9000 fold selective), with very litt1e somatostatin-like activity. NMR investigations have revealed that the side chain of D-Tic residue exists exclusively in a g- conformation. Disconnection of this methylene bridge via synthesis of {A figure is presented} gave an analogue that exhibited low affinity for the μ opioid receptor and greatly reduced selectivity. NMR investigations have uncovered a large participation of g+ and trans side chain conformations for the aromatic ring in the D-N-MePhe residue, and a more folded overall conformation. These results illustrate how constraint of side chain moieties of critical amino acid residues to a specific or "biased" conformation can provide important insights into the topological requirements for peptide-receptor interactions and can contribute to design of ligands for receptor mapping.

Original languageEnglish (US)
Pages (from-to)697-710
Number of pages14
JournalTetrahedron
Volume44
Issue number3
DOIs
StatePublished - 1988

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Narcotic Antagonists
Conformations
Ligands
Acids
Opioid Receptors
Cytidine Triphosphate
Peptide Receptors
Nuclear magnetic resonance
Tics
Peptide Hormones
Somatostatin
Amino Acids
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

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title = "A new approach to receptor ligand design: synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoouinoline carroxylic acid",
abstract = "Investigations of the physiological functions of opioid receptors (μ,δ,κ and others) require potent and selective receptor ligands. Conformational constraint provides a useful approach to increase receptor selectivity of flexible peptides. This approach reduces the set of low energy conformations accessible for the ligand and thus can provide insight into topologica1 features that may be responsible for high affinity to a particular receptor subtype. Using this approach, we describe a new class of potent and selective μ opioid receptor antagonists and demonstrate a new approach for the design of receptor specific ligands by which a low affinity, {"}non-physiological{"} activity of a natural peptide hormone is converted to a high potency, receptor selective ligand for that receptor, and, at the same time, eliminates the activity at the natural receptors for the peptide. Recently we reported the design and synthesis of a new class of μ opioid receptor selective antagonists, of which {A figure is presented}(CTP) was found to be among the most potent and selective, and {A figure is presented}(PCTP) exhibited a sharp decrease of affinity for μ receptors ( 100 foTd) and a modest increase ( 3 fold) in affinity for δ receptors. We now present 1h NMR evidence which suggests a more folded conformation for the latter compound. This result led to the design of further constrained analogues in which a methylene bridge is inserted between the α-amino group and the 2'position of the aromatic ring of n-phe1 in CTP. This analogue {A figure is presented}(TCTP) was found to be the most μ vs. δ receptor selective ligand known (> 9000 fold selective), with very litt1e somatostatin-like activity. NMR investigations have revealed that the side chain of D-Tic residue exists exclusively in a g- conformation. Disconnection of this methylene bridge via synthesis of {A figure is presented} gave an analogue that exhibited low affinity for the μ opioid receptor and greatly reduced selectivity. NMR investigations have uncovered a large participation of g+ and trans side chain conformations for the aromatic ring in the D-N-MePhe residue, and a more folded overall conformation. These results illustrate how constraint of side chain moieties of critical amino acid residues to a specific or {"}biased{"} conformation can provide important insights into the topological requirements for peptide-receptor interactions and can contribute to design of ligands for receptor mapping.",
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T2 - synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoouinoline carroxylic acid

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N2 - Investigations of the physiological functions of opioid receptors (μ,δ,κ and others) require potent and selective receptor ligands. Conformational constraint provides a useful approach to increase receptor selectivity of flexible peptides. This approach reduces the set of low energy conformations accessible for the ligand and thus can provide insight into topologica1 features that may be responsible for high affinity to a particular receptor subtype. Using this approach, we describe a new class of potent and selective μ opioid receptor antagonists and demonstrate a new approach for the design of receptor specific ligands by which a low affinity, "non-physiological" activity of a natural peptide hormone is converted to a high potency, receptor selective ligand for that receptor, and, at the same time, eliminates the activity at the natural receptors for the peptide. Recently we reported the design and synthesis of a new class of μ opioid receptor selective antagonists, of which {A figure is presented}(CTP) was found to be among the most potent and selective, and {A figure is presented}(PCTP) exhibited a sharp decrease of affinity for μ receptors ( 100 foTd) and a modest increase ( 3 fold) in affinity for δ receptors. We now present 1h NMR evidence which suggests a more folded conformation for the latter compound. This result led to the design of further constrained analogues in which a methylene bridge is inserted between the α-amino group and the 2'position of the aromatic ring of n-phe1 in CTP. This analogue {A figure is presented}(TCTP) was found to be the most μ vs. δ receptor selective ligand known (> 9000 fold selective), with very litt1e somatostatin-like activity. NMR investigations have revealed that the side chain of D-Tic residue exists exclusively in a g- conformation. Disconnection of this methylene bridge via synthesis of {A figure is presented} gave an analogue that exhibited low affinity for the μ opioid receptor and greatly reduced selectivity. NMR investigations have uncovered a large participation of g+ and trans side chain conformations for the aromatic ring in the D-N-MePhe residue, and a more folded overall conformation. These results illustrate how constraint of side chain moieties of critical amino acid residues to a specific or "biased" conformation can provide important insights into the topological requirements for peptide-receptor interactions and can contribute to design of ligands for receptor mapping.

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