167496-29-9Relevant academic research and scientific papers
Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988
Augelli-Szafran, Corinne E.,Horwell, David C.,Kneen, Clare,Ortwine, Daniel F.,Pritchard, Martyn C.,Purchase, Terri S.,Roth, Bruce D.,Trivedi, Bharat K.,Hill, David,Suman-Chauhan, Nirmala,Webdale, Louise
, p. 1733 - 1745 (2007/10/03)
A study of structure-activity relationships of a series of 'dipeptoid' CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-α-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum π near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.
Differences in backbone structure between angiotensin II agonists and type I antagonists
Matsoukas,Agelis,Wahhab,Hondrelis,Panagiotopoulos,Yamdagni,Wu,Mavromoustakos,Maia,Ganter,Moore
, p. 4660 - 4669 (2007/10/02)
Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(γ- OMe)] and δ-methoxy-L-norvaline [Nva(δ-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus, and their backbone conformational properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar1,HSer-(γ-OMe)8]ANGII, [HSer(γ-OMe)8]ANGII, [Des1,HSer(γ- OMe)8]ANGII, [Sar1,Nva(δ-OMe)8]-ANGII, and [Des1,Nva(δ-OMe)8]ANGII had, respectively, the following antagonist activities, pA2: 7.6, 7.5, 1]ANGII with δ-hydroxy-L-norvaline [Nva(δ- OH)], δ-methoxy-L-norvaline [Nva(δ-OMe)], 4'-carboxyphenylalanine [Phe(4'- COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(δ-OH)4]ANGII, [Aib1,Nva(δ-OMe)4]ANGII, [Sar1, DL-Phe(4'- COOH)4]ANGII, and [Sar1,DL-Phe(4'-CF3)4]ANGII had, respectively, agonist activities as follows: 4%, 1.5%, 3%, 8 in Sarilesin with the higher homologs HSer(γ-OMe) and Nva(δ-OMe) does not greatly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [Sar1]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be replaced by any negatively charged or electronegative group. Conformational investigation of the ANGII type I antagonists [HSer(γ- OMe)8]ANGII and [Sar1 Nva(δ-OMe)8]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found in ANGII and [Sar1]ANGII (J. Biol. Chem. 1994, 269, 5303) is not present in type I antagonists, providing for the first time an important conformational difference between angiotensin II agonists and type I antagonists.
