Simmons R D, Kaiser F C, Pierson M E, Rosamond J R
Pharmacology Department, Astra Arcus USA, Rochester, NY 14602, USA.
Pharmacol Biochem Behav. 1998 Feb;59(2):439-44. doi: 10.1016/s0091-3057(97)00446-2.
Cholecystokinin octapeptide (CCK-8) and the peptide analog ARL 14294, formerly FPL 14294, [Hpa(SO3H)-Met-Gly-Trp-Met-Asp-N(Me)Phe-NH2], have been reported to induce satiety by interaction with the CCK-A receptor subtype. ARL 15849 [Hpa(SO3H)-Nle-Gly-Trp-Nle-N(Me)-Asp-Phe-NH2] is an improved ARL 14294 analog with enhanced CCK-A receptor selectivity, greater stability, and a longer duration of action. The affinity of ARL 15849 for the CCK-A receptor (Ki = 0.034 nM) is 6,600 fold greater than for the CCK-B receptor (Ki = 224 nM), whereas CCK-8 and ARL 14294 are nonselective. Although comparable in potency to contract isolated gallbladder and induce pancreatic phosphatidylinositol hydrolysis, ARL 15849 is 3- and 100-fold more potent than ARL 14294 and CCK-8, respectively, to inhibit 3-h feeding in rats. The duration of feeding inhibition was significantly longer for ARL 15849 (>5 h), compared to equipotent doses of ARL 14294 (3 h), and CCK-8 (1 h). Intranasal administration of ARL 15849 inhibits feeding in beagle dogs with a greater separation between doses that induce emesis and those that inhibit feeding. Therefore, ARL 15849 is a potent, selective, intranasally active anorectic agent which may be useful in the treatment of eating disorders.
据报道，胆囊收缩素八肽（CCK-8）和肽类似物ARL 14294（原FPL 14294，[Hpa(SO3H)-Met-Gly-Trp-Met-Asp-N(Me)Phe-NH2]）通过与CCK-A受体亚型相互作用诱导饱腹感。ARL 15849 [Hpa(SO3H)-Nle-Gly-Trp-Nle-N(Me)-Asp-Phe-NH2]是一种改良的ARL 14294类似物，具有增强的CCK-A受体选择性、更高的稳定性和更长的作用持续时间。ARL 15849对CCK-A受体的亲和力（Ki = 0.034 nM）比对CCK-B受体的亲和力（Ki = 224 nM）高6600倍，而CCK-8和ARL 14294则无选择性。尽管在收缩离体胆囊和诱导胰腺磷脂酰肌醇水解的效力方面相当，但ARL 15849在抑制大鼠3小时进食方面的效力分别比ARL 14294和CCK-8高3倍和100倍。与等效剂量的ARL 14294（3小时）和CCK-8（1小时）相比，ARL 15849的进食抑制持续时间明显更长（>5小时）。鼻内给予ARL 15849可抑制比格犬的进食，诱导呕吐的剂量与抑制进食的剂量之间的差距更大。因此，ARL 15849是一种强效、选择性、鼻内活性的食欲抑制剂，可能对饮食失调的治疗有用。
