Development of a model for the δ opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the Cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13)

Henry I. Mosberg, John R. Omnaas, Andrei Lomize, Deborah L. Heyl, Ian Nordan, Carol Mousigian, Peg Davis, Frank Porreca

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Abstract

The in vitro pharmacological properties and conformational features of analogs of the δ opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of β-methylphenylalanine β-MePhe) were investigated. Both analogs in which the α carbon of the Phe3 replacement has L-stereochemistry display high affinity for δ receptors with the (2S,3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S,3S)-MePhe3 diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe3 analog, also displays high affinity for the δ receptor and is extraordinarily selective for this receptor. All analogs were agonists in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle bioassays, displaying MVD and GPI potencies consistent with their δ and μ opioid receptor affinities, respectively. The use of β-MePhe as a replacement for Phe3 was based upon the desire to reduce the conformational flexibility of the Phe3 side chain by imposing a steric rotational constraint in the form of the β-methyl substituent and to thus deduce the residue 3 side chain orientation in the δ receptor-bound conformation from the correlation between δ receptor binding affinities and conformational preferences. Molecular mechanics computations revealed, however, that the conformational constraints imposed by the β-methyl group in the (2S,3S)-MePhe3 and (2S,3A)-MePhe3 analogs were too modest to allow unequivocal determination of δ receptor-bound residue 3 side chain conformation. However, analysis of the high-affinity (2R,3R)-MePhe3 analog revealed a strong preference for a single side chain conformer (χ1 ∼ 60°). Low-energy conformers of this analog could only be effectively superimposed with low-energy conformers of the parent peptide in which the Phe3 side chain conformation was limited to χ1 ∼ -60°. This observation eliminates the last remaining uncertainty regarding conformational features of the pharmacophore elements in the δ receptor-bound state, allowing the proposal of a complete model.

Original languageEnglish (US)
Pages (from-to)4384-4391
Number of pages8
JournalJournal of Medicinal Chemistry
Volume37
Issue number25
StatePublished - 1994

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Vas Deferens
Opioid Receptors
Ileum
Conformations
Guinea Pigs
Stereochemistry
Molecular Computers
Stereoisomerism
Mechanics
Biological Assay
Uncertainty
Smooth Muscle
Molecular mechanics
Carbon
Bioassay
Pharmacology
Crystal orientation
Peptides
Muscle
H-tyrosyl-cyclo(cysteinyl-phenylalanyl-penicillaminyl)-OH

ASJC Scopus subject areas

  • Organic Chemistry

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Development of a model for the δ opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the Cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). / Mosberg, Henry I.; Omnaas, John R.; Lomize, Andrei; Heyl, Deborah L.; Nordan, Ian; Mousigian, Carol; Davis, Peg; Porreca, Frank.

In: Journal of Medicinal Chemistry, Vol. 37, No. 25, 1994, p. 4384-4391.

Research output: Contribution to journalArticle

Mosberg, Henry I. ; Omnaas, John R. ; Lomize, Andrei ; Heyl, Deborah L. ; Nordan, Ian ; Mousigian, Carol ; Davis, Peg ; Porreca, Frank. / Development of a model for the δ opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the Cyclic δ receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 25. pp. 4384-4391.
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abstract = "The in vitro pharmacological properties and conformational features of analogs of the δ opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of β-methylphenylalanine β-MePhe) were investigated. Both analogs in which the α carbon of the Phe3 replacement has L-stereochemistry display high affinity for δ receptors with the (2S,3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S,3S)-MePhe3 diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe3 analog, also displays high affinity for the δ receptor and is extraordinarily selective for this receptor. All analogs were agonists in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle bioassays, displaying MVD and GPI potencies consistent with their δ and μ opioid receptor affinities, respectively. The use of β-MePhe as a replacement for Phe3 was based upon the desire to reduce the conformational flexibility of the Phe3 side chain by imposing a steric rotational constraint in the form of the β-methyl substituent and to thus deduce the residue 3 side chain orientation in the δ receptor-bound conformation from the correlation between δ receptor binding affinities and conformational preferences. Molecular mechanics computations revealed, however, that the conformational constraints imposed by the β-methyl group in the (2S,3S)-MePhe3 and (2S,3A)-MePhe3 analogs were too modest to allow unequivocal determination of δ receptor-bound residue 3 side chain conformation. However, analysis of the high-affinity (2R,3R)-MePhe3 analog revealed a strong preference for a single side chain conformer (χ1 ∼ 60°). Low-energy conformers of this analog could only be effectively superimposed with low-energy conformers of the parent peptide in which the Phe3 side chain conformation was limited to χ1 ∼ -60°. This observation eliminates the last remaining uncertainty regarding conformational features of the pharmacophore elements in the δ receptor-bound state, allowing the proposal of a complete model.",
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