Abstract
(S)-4-(Carboxamido)phenylalanine (Cpa) is examined as a bioisosteric replacement for the terminal tyrosine (Tyr) residue in a variety of known peptide ligands for the mu, delta and kappa opioid receptors. The Cpa-containing peptides, assayed against cloned human opioid receptors, display comparable binding affinity (Ki), and agonist potency (EC50) to the parent ligands at the three receptors. Cpa analogs of delta selective peptides show an increase in delta selectivity relative to the mu receptor. Cpa is the first example of an amino acid that acts as a surrogate for Tyr in opioid peptide ligands, challenging the long-standing belief that a phenolic residue is required for high affinity binding.
MeSH terms
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Amino Acids, Aromatic / chemical synthesis
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Amino Acids, Aromatic / pharmacology
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Analgesics, Opioid / chemical synthesis*
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Analgesics, Opioid / pharmacology
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Binding Sites
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Cell Line
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Humans
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Ligands
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Molecular Structure
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Opioid Peptides / metabolism
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Phenol / chemistry
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemical synthesis*
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Phenylalanine / pharmacology
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Receptors, Opioid, delta / drug effects
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Receptors, Opioid, delta / metabolism*
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Receptors, Opioid, kappa / drug effects
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Receptors, Opioid, kappa / metabolism*
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Receptors, Opioid, mu / drug effects
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Receptors, Opioid, mu / metabolism*
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Tyrosine / pharmacology*
Substances
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(4-carboxamido)phenylalanine
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Amino Acids, Aromatic
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Analgesics, Opioid
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Ligands
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Opioid Peptides
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Receptors, Opioid, delta
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Phenol
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Tyrosine
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Phenylalanine