Augelli-Szafran C E, Horwell D C, Kneen C, Ortwine D F, Pritchard M C, Purchase T S, Roth B D, Trivedi B K, Hill D, Suman-Chauhan N, Webdale L
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Bioorg Med Chem. 1996 Oct;4(10):1733-45. doi: 10.1016/0968-0896(96)00185-x.
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]-alpha-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 pi 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.
对一系列“二肽类”CCK - B受体拮抗剂进行了构效关系研究，其中在保持强效拮抗剂CI - 988的[(2 - 金刚烷氧基)羰基]-α-甲基-R)-色氨酸部分不变的情况下，研究了苯环的变化。由于本研究的主要重点是苯取代基的变化，因此采用了系列设计技术以确保物理化学性质（亲脂性、空间位阻、电子性质）以及位置取代有足够的分布范围。对26个和16个类似物的定量构效关系分析表明，CCK - B亲和力与苯环取代基的总体大小以及略微的亲脂性有关（即较小的基团分别与最佳π值接近零时效力的增加相关）。进一步的探索表明，对苯取代基的尺寸和电子性质可能与CCK - B亲和力有关。短的、庞大的（支链的）吸电子基团显示出亲和力增加。对位有小取代基的类似物似乎对CCK - B有大约1000倍的选择性，表明对CCK - B结合的选择性对苯环取代敏感。从本研究中得到的4 - F - 苯基二肽类在CCK - B受体处具有极高的亲和力（IC50 = 0.08 nM），并且也具有很高的选择性（对CCK - B有940倍的选择性）。与先前的报道一致，发现取代苯乙酰胺中心的(S)-构型、羧酸以及苯环的存在与CCK - A和CCK - B受体处亲和力的增加有关。
