Analogs of the Delta Opioid Receptor Selective Cyclic Peptide [2-D-penicillamine,5-D-penicillamine]-enkephalin: 2',6'-dimethyltyrosine and Gly3-Phe4 Amide Bond Isostere Substitutions

J Med Chem. 1992 Aug 7;35(16):2928-38. doi: 10.1021/jm00094a002.

Abstract

In order to develop systemically-active opioid peptides, the delta-selective, opioid pentapeptide [D-Pen2,D-Pen5]-enkephalin (DPDPE) was modified by esterification and by substitution of 2',6'-dimethyltyrosine for tyrosine to yield 4. Compound 4 was on the order of 8- and 800-fold more active than DPDPE in both delta and mu opioid radioligand binding assays, respectively, in rat neural membrane suspensions. Compound 4 was considerably more potent than DPDPE at inhibiting contractions of electrically-stimulated mouse vas deferens in vitro, and this effect was very sensitive to naltrindole, a delta-selective opioid antagonist. These observations can be taken as indication that 4 exerts its effects through delta opioid receptors. This interpretation is supported by the finding that the EC50 value of 4 derived in the smooth muscle assay is very similar to that derived in NG108-15 neuroblastoma cells, a preparation devoid of mu receptors. Unlike DPDPE, 4 exhibited significant, naloxone-sensitive, antinociceptive activity when administered systemically, as measured by inhibition of phenylbenzquinone-induced stretching in mice (ED50 = 2.1 mg/kg). Compound 4 also displayed significant antinociceptive activity following systemic administration as measured by its action in mice to increase latencies for tail withdrawal from radiant heat (ED50 = 50 mg/kg). Compound 4 did not produce morphine-like discriminative stimulus effects in rats trained to discriminate 3.0 mg/kg morphine from vehicle at doses ranging from 30 to 120 mg/kg. This observation can be interpreted as indication that within this dosage range there is an absence of morphine-like subjective effects. Physical dependence, however, could be induced in mice at higher doses of 4 under a progressively-graded, 4-day dose regimen. Congeners of 4 with amide bond surrogates for the Gly-Phe amide bond (oxymethylene, trans-double bond, and bismethylene isosteres) in the cyclic core of DPDPE were prepared in an attempt to increase the antinociceptive activity of 4. While some of the congeners were active in the in vitro assays, they did not display significant antinociceptive activity following systemic administration. The preparation of all the compounds was accomplished by solution-phase methods. The mechanisms which might underlie the biological and systemic activity of 4 are discussed.

MeSH terms

  • Amides / chemistry
  • Amino Acid Sequence
  • Analgesics / metabolism
  • Analgesics / pharmacology
  • Animals
  • Enkephalin, D-Penicillamine (2,5)-
  • Enkephalins / chemistry*
  • Enkephalins / metabolism
  • Enkephalins / pharmacology
  • Glycine / chemistry
  • Male
  • Mice
  • Molecular Sequence Data
  • Muscle Contraction / drug effects
  • Neuroblastoma
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacology
  • Phenylalanine / chemistry
  • Radioligand Assay
  • Rats
  • Rats, Inbred Strains
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, delta
  • Structure-Activity Relationship
  • Substrate Specificity
  • Tumor Cells, Cultured
  • Tyrosine / analogs & derivatives*
  • Tyrosine / chemistry
  • Vas Deferens / physiology

Substances

  • Amides
  • Analgesics
  • Enkephalins
  • Peptides, Cyclic
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • 2',6'-dimethyltyrosine
  • Tyrosine
  • Phenylalanine
  • Enkephalin, D-Penicillamine (2,5)-
  • Glycine