Pierson M E, Comstock J M, Simmons R D, Kaiser F, Julien R, Zongrone J, Rosamond J D
Astra Arcus USA, Rochester, New York 14602, USA.
J Med Chem. 1997 Dec 19;40(26):4302-7. doi: 10.1021/jm970477u.
Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.
胆囊收缩素（CCK）是一种由33个氨基酸组成的肽，在中枢神经系统（通过CCK-B受体）和外周（通过CCK-A受体）具有多种功能。CCK通过A受体亚型介导饱腹感，提示其在肥胖管理中发挥作用。羧基末端八肽（CCK-8）在这方面具有完全活性，但缺乏受体选择性、代谢稳定性和口服生物利用度。将Asp7的手性翻转并结合Phe8的N-甲基化产生化合物5，其对CCK-A受体表现出高亲和力和2100倍的选择性。化合物6（Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2）通过将N-甲基基团从Phe转移到Asp衍生而来，在不影响CCK-A亲和力的情况下，显著降低了CCK-B亲和力，得到了对CCK-A受体具有6600倍选择性的化合物。在禁食大鼠腹腔注射后，这些化合物以纳摩尔效力抑制食物摄入。除了效力更强外，化合物6连续九天给药时可使大鼠体重减轻。鼻内给予6可有效抑制比格犬的进食。化合物6通过CCK-A受体系统产生有效的厌食活性。
