Single point D-substituted corticotropin-releasing factor analogues: effects on potency and physicochemical characteristics

J Med Chem. 1993 Oct 1;36(20):2851-9. doi: 10.1021/jm00072a003.

Abstract

In an attempt to determine which conformational parameters are important for the biological activity of ovine corticotropin-releasing factor (oCRF), we have synthesized in significant amounts (50-200 mg) and characterized chemically, structurally (CD), and biologically, oCRF analogues with substitution of each amino acid by its corresponding D-isomer. Out of 37 of these analogues, three were found to be equipotent to, or twice as potent as, oCRF, 13 had potencies in the range from 10 to 60%, 17 had potencies ranging from 1 to 10%, and the four others had potencies less than 0.5%. None of the analogues antagonized oCRF-induced release of ACTH in vitro at concentrations > or = 1000 oCRF. Since antagonists to CRF action can be generated by deletion of the first 8-14 residues, a series of CRF antagonists which exhibit significantly higher in vitro and in vivo biological potency than [Met18,Lys23,Glu27,29,40,Ala32,41,-Leu33,3 6,38] h/rCRF, [alpha-helical-CRF9-41], is also described. [D-Phe12,Nle21,38,Arg36]h/rCRF, in particular, was found to be ca. 15 times more potent than alpha-helical-CRF9-41 in vitro. In the rat, however, this analogue was about as effective as alpha-helical-CRF9-41 in blocking CRF-induced decrease in mean arterial blood pressure and increase in heart rate. Its potency in blocking epinephrine release by CRF was not significantly different from that of alpha-helical-CRF9-41. In the adrenalectomized rat, [Lys36]alpha-helical-CRF(9-41) (1.7 mg/kg) blunted the effect of endogenous CRF over a 90-min period; by comparison, a similar dose of alpha-helical-CRF9-41 was effective for less than 1 h.

Publication types

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

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Amino Acid Sequence
  • Animals
  • Blood Pressure / drug effects
  • Circular Dichroism
  • Corticotropin-Releasing Hormone / analogs & derivatives*
  • Corticotropin-Releasing Hormone / chemistry
  • Corticotropin-Releasing Hormone / pharmacology
  • Epinephrine / blood
  • Heart Rate / drug effects
  • Male
  • Molecular Sequence Data
  • Norepinephrine / blood
  • Peptides / chemical synthesis
  • Peptides / pharmacology
  • Protein Structure, Secondary
  • Rats
  • Rats, Sprague-Dawley
  • Sheep
  • Structure-Activity Relationship

Substances

  • Peptides
  • Adrenocorticotropic Hormone
  • Corticotropin-Releasing Hormone
  • Norepinephrine
  • Epinephrine