Criscione L, Rigollier P, Batzl-Hartmann C, Rüeger H, Stricker-Krongrad A, Wyss P, Brunner L, Whitebread S, Yamaguchi Y, Gerald C, Heurich R O, Walker M W, Chiesi M, Schilling W, Hofbauer K G, Levens N
Metabolic and Cardiovascular Diseases Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. Leoluca.criscione@pharma,novartis.com
J Clin Invest. 1998 Dec 15;102(12):2136-45. doi: 10.1172/JCI4188.
The new neuropeptide Y (NPY) Y5 receptor antagonist CGP 71683A displayed high affinity for the cloned rat NPY Y5 subtype, but > 1, 000-fold lower affinity for the cloned rat NPY Y1, Y2, and Y4 subtypes. In LMTK cells transfected with the human NPY Y5 receptor, CGP 71683A was without intrinsic activity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given intraperitoneally (dose range 1-100 mg/kg) to a series of animal models of high hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 71683A dose-dependently inhibited food intake. During the dark phase, CGP 71683A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4. Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The data demonstrate that the NPY Y5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulatory mechanisms are induced to restore appetite.
新型神经肽Y（NPY）Y5受体拮抗剂CGP 71683A对克隆的大鼠NPY Y5亚型表现出高亲和力，但对克隆的大鼠NPY Y1、Y2和Y4亚型的亲和力低1000倍以上。在转染了人NPY Y5受体的LMTK细胞中，CGP 71683A无内在活性，并拮抗NPY诱导的Ca2+瞬变。将CGP 71683A腹腔注射（剂量范围为1 - 100 mg/kg）给予一系列下丘脑NPY水平高的动物模型。在瘦的饱食大鼠中，CGP 71683A显著拮抗脑室内注射NPY引起的食物摄入量增加。在禁食24小时和链脲佐菌素诱导的糖尿病大鼠中，CGP 71683A剂量依赖性地抑制食物摄入。在黑暗期，CGP 71683A剂量依赖性地抑制自由进食的瘦大鼠的食物摄入，而不影响正常的食物摄入模式或诱发味觉厌恶。在自由进食的瘦大鼠中，腹腔注射CGP 71683A 28天剂量依赖性地抑制食物摄入，在第3天和第4天观察到最大减少量。尽管食物摄入量恢复到对照水平，但体重和外周脂肪量仍显著降低。数据表明，NPY Y5受体亚型在NPY诱导的食物摄入中起作用，但也表明，长期阻断会诱导反调节机制来恢复食欲。
