title: (4-Carboxamido)phenylalanine is a surrogate for tyrosine in opioid receptor peptide ligands.
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.
authors.affiliation: Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. rdolle@adolor.com
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
authors.forename: Mathieu
authors.initials: M
authors.lastname: Machaut
authors.forename: Blanca
authors.initials: B
authors.lastname: Martinez-Teipel
authors.forename: Serge
authors.initials: S
authors.lastname: Belanger
authors.forename: Joel A
authors.initials: JA
authors.lastname: Cassel
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Stabley
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Graczyk
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
mesh_terms: D024322:Amino Acids, Aromatic / Q000138:chemical synthesis / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018847:Opioid Peptides / Q000378:metabolism; D019800:Phenol / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D014443:Tyrosine / Q000494:pharmacology*
chemical_list: C495750:(4-carboxamido)phenylalanine; D024322:Amino Acids, Aromatic; D000701:Analgesics, Opioid; D008024:Ligands; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019800:Phenol; D014443:Tyrosine; D010649:Phenylalanine