@article {McFadyen960, author = {Iain J. McFadyen and Katarzyna Sobczyk-Kojiro and Michael J. Schaefer and Jeffrey C. Ho and John R. Omnaas and Henry I. Mosberg and John R. Traynor}, title = {Tetrapeptide Derivatives of [d-Pen2,d-Pen5]-Enkephalin (DPDPE) Lacking an N-Terminal Tyrosine Residue Are Agonists at the μ-Opioid Receptor }, volume = {295}, number = {3}, pages = {960--966}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The Phe1 cyclic tetrapeptide Phe-c[d-Cys-Phe-d-Pen]NH2(Et) (JH-54) has been shown previously to exhibit high affinity and selectivity for the μ-opioid receptor. To examine the role of the Phe1 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 [35S]GTPγS assay. Alteration of the bridging groups between the d-Cys2 andd-Pen4 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 μ- and δ-affinities. The one carbon distance between the α carbon and phenyl ring in the N-terminal residue was critical. Additional steric bulk in the N-terminal Phe1 residue was accommodated without large reductions in affinity in two naphthyl analogs, but not with 3,3-(diphenyl)alanine. Conformational restriction of the Cα-Cβ and/or Cβ-Cγ 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 phenylproline1-containing peptides. Most surprisingly, replacement of the Phe1 aromatic ring with cyclohexyl resulted in a peptide of moderate affinity (Ki = 32.5 nM) and potency (EC50 = 58.8 nM). Thus, the tyrosylpara-hydroxyl substituent and even aromaticity in the N-terminal amino acid of these tetrapeptides are shown to be important, but not critical, features for μ-opioid receptor affinity, agonist potency, and efficacy. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/295/3/960}, eprint = {https://jpet.aspetjournals.org/content/295/3/960.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }