Félétou Michel, Levens Nigel R
Department of Angiology, Institut de Recherches Servier, Suresnes, France.
Curr Opin Investig Drugs. 2005 Oct;6(10):1002-11.
During the past decade, a detailed understanding has emerged of the aminergic and peptidergic neural pathways present within the brain that regulate appetite. Central among the peptide regulators is neuropeptide Y (NPY), a potent orexigenic agent that acts through five different receptor subtypes. Efforts to find novel appetite suppressant drugs that inhibit the interaction of NPY with either the NPY Y1 or NPY Y5 receptor subtypes have proven disappointing. Attempts have now been made to identify an NPY Y2 stimulator that will suppress appetite. Within the hypothalamus, NPY Y2 receptors have a predominantly presynaptic location where they act to inhibit NPY release. Stimulation of NPY Y2 receptors with synthetic peptide ligands or the gut derived peptide PY3-36 has been shown to reduce food intake. The NPY Y2 receptor has a wide distribution both within the brain and in the periphery. Stimulation of the NPY Y2 subtype at these sites produces a wide array of effects unrelated to changes in food intake. In consequence, the administration of both endogenous and exogenous agonists of the NPY Y2 receptor is likely to cause side effects, particularly regarding pituitary hormone release, as well as on the cardiovascular and gastrointestinal systems. The possibility that long-term NPY Y2 agonism could cause bone thinning and retinal angiogenesis are of particular concern and will need to be investigated as drug discovery moves forward.
在过去十年中，人们对大脑中调节食欲的胺能和肽能神经通路有了详细的了解。肽调节剂中核心的是神经肽Y（NPY），它是一种强效的促食欲剂，通过五种不同的受体亚型发挥作用。寻找能抑制NPY与NPY Y1或NPY Y5受体亚型相互作用的新型食欲抑制药物的努力已被证明令人失望。现在已经尝试寻找一种能抑制食欲的NPY Y2激动剂。在下丘脑中，NPY Y2受体主要位于突触前，其作用是抑制NPY的释放。用合成肽配体或肠道衍生肽PY3-36刺激NPY Y2受体已被证明可减少食物摄入量。NPY Y2受体在大脑和外周均有广泛分布。在这些部位刺激NPY Y2亚型会产生一系列与食物摄入量变化无关的效应。因此，给予NPY Y2受体的内源性和外源性激动剂都可能引起副作用，特别是对垂体激素释放以及心血管和胃肠道系统的影响。长期NPY Y2激动可能导致骨质变薄和视网膜血管生成的可能性尤其令人担忧，随着药物研发的推进，需要对此进行研究。
