Conformational Restriction of the Phenylalanine Residue in a Cyclic Opioid Peptide Analogue: Effects on Receptor Selectivity and Stereospecificity

J Med Chem. 1991 Oct;34(10):3125-32. doi: 10.1021/jm00114a023.

Abstract

In an effort to determine the effect of side chain conformational restriction on opioid receptor selectivity, the cyclic phenylalanine analogues 2-aminoindan-2-carboxylic acid (Aic), 2-aminotetralin-2-carboxylic acid (Atc), and tetrahydroisoquinoline-3-carboxylic acid (Tic) were substituted for Phe in the potent cyclic opioid peptide analogue H-Tyr-D-Orn-Phe-Glu-NH2, which lacks significant opioid receptor selectivity. Compounds were tested in mu- and delta-opioid receptor representative binding assays and bioassays in vitro. The analogue H-Tyr-D-Orn-Aic-Glu-NH2 was found to be a potent agonist with high preference of mu receptors over delta receptors. Opening of the five-membered ring of Aic in the latter peptide, as achieved through substitution of C alpha-methylphenylalanine or o-methylphenylalanine, resulted in only slightly selective compounds, indicating that the high mu selectivity of the Aic analogue is exclusively the consequence of the imposed side chain conformational restriction. Both diastereoisomers of H-Tyr-D-Orn-(D,L)-Atc-Glu-NH2 were highly mu-selective and, in contrast to the weak affinity observed with the D-Phe3 analogue as compared to the L-Phe3 analogue, both had similar potency. Thus, stereospecificity was lost as a consequence of side chain conformational restriction. Further structure-activity data obtained with analogues containing L- or D-homophenylalanine (Hfe) or 3-(1'-naphthyl)alanine (Nap) in place of Phe3 and consideration of geometric interrelationships between Nap and the L and D isomers of Atc, Hfe, and Phe led to the proposal that the D-Phe3 and the D-Atc3 analogue may have different modes of binding to the receptor. The very low potency observed with H-Tyr-D-Orn-N alpha MePhe-Glu-NH2 (N alpha MePhe = N alpha-methylphenylalanine) and H-Tyr-D-Orn-Tic-Glu-NH2 indicated that N alpha-alkylation at the 3-position is detrimental to activity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Assay
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Cyclization
  • Endorphins / chemistry*
  • Endorphins / metabolism
  • Endorphins / pharmacology
  • Guinea Pigs
  • Indans / chemistry
  • Isoquinolines / chemistry
  • Mice
  • Molecular Conformation
  • Molecular Sequence Data
  • Muscle Contraction / drug effects
  • Muscle, Smooth / physiology
  • Phenylalanine / chemistry*
  • Rats
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*
  • Tetrahydronaphthalenes / chemistry

Substances

  • Endorphins
  • Indans
  • Isoquinolines
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Tetrahydroisoquinolines
  • Tetrahydronaphthalenes
  • 2-aminoindan
  • 2-aminotetralin
  • Phenylalanine
  • 1,2,3,4-tetrahydroisoquinoline