| 11082429 |
McFadyen IJ, Sobczyk-Kojiro K, Schaefer MJ, Ho JC, Omnaas JR, Mosberg HI, Traynor JR: Tetrapeptide derivatives of [D-Pen (2),D-Pen (5)]-enkephalin (DPDPE) lacking an N-terminal tyrosine residue are agonists at the mu-opioid receptor. J Pharmacol Exp Ther. 2000 Dec;295(3):960-6.
The Phe (1) cyclic tetrapeptide Phe-c [D-Cys-Phe-D-Pen] NH (2) (Et) (JH-54) has been shown previously to exhibit high affinity and selectivity for the mu-opioid receptor. To examine the role of the Phe (1) residue in the unexpected high affinity of this peptide, 11 analogs of JH-54 have been synthesized and evaluated for opioid ligand binding and for efficacy using the [(35) S] GTPgammaS assay. Alteration of the bridging groups between the D-Cys (2) and D-Pen (4) residues of JH-54 from dithioether to disulfide revealed the importance of the relative position of the aromatic rings of the first and third residues in determining mu- and delta-affinities. The one carbon distance between the alpha carbon and phenyl ring in the N-terminal residue was critical. Additional steric bulk in the N-terminal Phe (1) residue was accommodated without large reductions in affinity in two naphthyl analogs, but not with 3, 3-(diphenyl) alanine. Conformational restriction of the Calpha-Cbeta and/or Cbeta-Cgamma bonds had little effect on affinities in two peptides with 2-amino-2-carboxytetralin in position 1, but it abolished activity in an isoquinoline analog and differentially altered activity in four phenylproline (1)-containing peptides. Most surprisingly, replacement of the Phe (1) aromatic ring with cyclohexyl resulted in a peptide of moderate affinity (K (i) = 32.5 nM) and potency (EC (50) = 58.8 nM). Thus, the tyrosyl para-hydroxyl substituent and even aromaticity in the N-terminal amino acid of these tetrapeptides are shown to be important, but not critical, features for mu-opioid receptor affinity, agonist potency, and efficacy. |
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