SYNTHESIS AND RELATIVE POTENCIES OF NEW CONSTRAINED CRF ANTAGONISTS

被引:81
作者
HERNANDEZ, JF [1 ]
KORNREICH, W [1 ]
RIVIER, C [1 ]
MIRANDA, A [1 ]
YAMAMOTO, G [1 ]
ANDREWS, J [1 ]
TACHE, Y [1 ]
VALE, W [1 ]
RIVIER, J [1 ]
机构
[1] SALK INST BIOL STUDIES, CLAYTON FDN, PEPTIDE BIOL LABS, 10010 N TORREY PINES RD, LA JOLLA, CA 92037 USA
关键词
D O I
10.1021/jm00072a004
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Two series of CRF antagonists with N(alpha)- and C(alpha)-methylated alanine and leucines were evaluated for their biological activities in vitro and in vivo in several systems. The poly-N-methylated analogue of alpha-helical-CRF9-41, [N(alpha)MeLeu10,15,27,37,N(alpha)MeAla22,32,41]-alpha-Hel-CRF9-41, was found to be considerably less potent than the parent non-N-methylated analogue. This result was expected on the basis that alpha-helicity was thought to be required for biological activity and the prediction that backbone substitutions on the nitrogen have a tendency to break alpha-helices (a hypothesis that was confirmed by circular dichroism). Next, a series of constrained analogues of the potent CRF antagonist, [DPhe12,Nle21,38]h/rCRF12-41, was synthesized that contained C(alpha)-methylleucine and/or C(alpha)-methylalanine (Aib) residues at selected positions. Because C(alpha)-methylation is recognized to increase alpha-helicity, and because there is now strong NMR data suggesting that residues 6-36 assume a well-defined alpha-helix, it was expected that these analogues would be more potent. Although usual solid-phase peptide synthesis procedures were followed, success in coupling the C(alpha)-methyl amino acids was obtained only with a 1:1 mixture of BOP/HOBt. In vitro potencies of the synthesized compounds were measured in a collagenase-dispersed anterior pituitary cell culture bioassay. Monosubstituted analogues were shown to be twice to one fourth as potent as the parent compound; while the pluri-substituted peptides were slightly less potent. This decrease in potency might be correlated to an unexpected lower helical content of the pluri-substituted compounds (as determined by CD spectroscopy), as it was suggested that the bioactive conformation of the CRF was predominantly alpha-helical. Interestingly, one analogue, [DPhe12,Nle21,38,C(alpha)-MeLeU37]h/rCRF12-41, was found to be more potent and longer acting than the parent compound in two in vivo assays measuring ACTH release after intravenous administration to adrenalectomized rats and reversal of stress-induced delay in gastric emptying in the rat after intracisternal administration. The molecular basis for this increased duration of action and potency is being investigated.
引用
收藏
页码:2860 / 2867
页数:8
相关论文
共 59 条
  • [1] OPTICAL ENANTIOMORPHS OF ISOVALINE
    BAKER, CG
    FU, SCJ
    BIRNBAUM, SM
    SOBER, HA
    GREENSTEIN, JP
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1952, 74 (18) : 4701 - 4702
  • [2] STEREOCHEMISTRY OF PEPTIDES CONTAINING 1-AMINOCYCLOPENTANECARBOXYLIC ACID (ACC5) - SOLUTION AND SOLID-STATE CONFORMATIONS OF BOC-ACC5-ACC5-NHME
    BARDI, R
    PIAZZESI, AM
    TONIOLO, C
    BALARAM, P
    [J]. BIOPOLYMERS, 1986, 25 (09) : 1635 - 1644
  • [3] ABDOMINAL SURGERY-INDUCED DELAYED GASTRIC-EMPTYING IN RATS - ROLE OF CRF AND SENSORY NEURONS
    BARQUIST, E
    ZINNER, M
    RIVIER, J
    TACHE, Y
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 262 (04): : G616 - G620
  • [4] The formation and stabillity of spiro-compounds. Part I. Spiro-compounds from cyclo-hexane.
    Beesley, RM
    Ingold, CK
    Thorpe, JF
    [J]. JOURNAL OF THE CHEMICAL SOCIETY, 1915, 107 : 1080 - 1106
  • [5] STRUCTURAL VERSATILITY OF PEPTIDES FROM C-ALPHA,ALPHA-DIALKYLATED GLYCINES - LINEAR AC3C HOMO-OLIGOPEPTIDES
    BENEDETTI, E
    DIBLASIO, B
    PAVONE, V
    PEDONE, C
    SANTINI, A
    CRISMA, M
    VALLE, G
    TONIOLO, C
    [J]. BIOPOLYMERS, 1989, 28 (01) : 175 - 184
  • [6] SYNTHESIS AND HYPERTENSIVE ACTIVITY OF NEUROPEPTIDE-Y FRAGMENTS AND ANALOGS WITH MODIFIED N-TERMINI OR C-TERMINI OR D-SUBSTITUTIONS
    BOUBLIK, JH
    SCOTT, NA
    BROWN, MR
    RIVIER, JE
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1989, 32 (03) : 597 - 601
  • [7] BROWN MR, 1991, STRESS NEUROBIOLOGY, P193
  • [8] BRUCKNER H, 1987, J CHROMATOGR, V386, P251, DOI 10.1016/S0021-9673(01)94602-3
  • [9] CASTRO B, 1975, TETRAHEDRON LETT, P1219
  • [10] CIRCULAR DICHROIC ANALYSIS OF PROTEIN CONFORMATION - INCLUSION OF BETA-TURNS
    CHANG, CT
    WU, CSC
    YANG, JT
    [J]. ANALYTICAL BIOCHEMISTRY, 1978, 91 (01) : 13 - 31