Danho W, Makofske R C, Swistok J, Michalewsky J, Gabriel T, Marks N, Berg M J, Baird L, Geiler V, Mackie G
Peptide Research Department, Hoffmann-La Roche, Nutley, NJ 07110.
Pept Res. 1991 Mar-Apr;4(2):59-65.
Analogs of cholecystokinin (CCK-7) in which the N-terminal Tyr(SO3H) was acetylated, Asp6 replaced with Thr(SO3H) and Phe7 replaced with N-methyl-Phe were prepared by solid-phase peptide synthesis and evaluated for their receptor-binding activity and ability to suppress appetite. The receptor binding activities of these synthetic analogs of CCK-7 and their selectivity for the CCK-A and CCK-B receptor subtypes were determined using solubilized membrane preparations from rat pancreatic tissue and bovine striatum. The synthetic peptide Ac-Tyr(SO3H)-Met-Gly-Trp-Met-Thr(SO3H)-N-methyl-Phe-NH2 (referred to as Ro 23-7014) demonstrated superior satiating potency (ED50 = 0.3 micrograms/kg, i.p.), increased selectivity for CCK-A receptors (400-fold), increased resistance to peptidergic degradation and a longer duration of action (4 to 5 hours). This analog also effectively suppressed food intake following intranasal administration (ED50 = 100 micrograms/kg). These studies demonstrate the feasibility of designing analogs of CCK-8 with greater selectivity, potency and duration of action, which may be useful as nonsystemically administered appetite suppressants.
通过固相肽合成法制备了胆囊收缩素（CCK-7）类似物，其中N端的Tyr(SO3H)被乙酰化，Asp6被Thr(SO3H)取代，Phe7被N-甲基-Phe取代，并对其受体结合活性和抑制食欲的能力进行了评估。使用大鼠胰腺组织和牛纹状体的可溶性膜制剂，测定了这些CCK-7合成类似物的受体结合活性及其对CCK-A和CCK-B受体亚型的选择性。合成肽Ac-Tyr(SO3H)-Met-Gly-Trp-Met-Thr(SO3H)-N-甲基-Phe-NH2（称为Ro 23-7014）表现出卓越的饱腹感效力（ED50 = 0.3微克/千克，腹腔注射），对CCK-A受体的选择性增加（400倍），对肽能降解的抗性增加，作用持续时间更长（4至5小时）。该类似物经鼻内给药后也能有效抑制食物摄入（ED50 = 100微克/千克）。这些研究证明了设计具有更高选择性、效力和作用持续时间的CCK-8类似物的可行性，这些类似物可用作非全身给药的食欲抑制剂。
