NOVEL ACTIONS OF INVERSE AGONISTS

目前有相当大的兴趣和辩论，是否逆激动剂代表仅仅是一个药理学的好奇心，或者他们是否有生理相关的行动和治疗潜力。 这场争论的出现是因为反向激动作用主要在受体过度表达或突变（组成型活性突变体）的人工系统中得到证实。 在这些非天然系统中，反向激动剂通常由于降低配体非依赖性（组成型）受体活性而降低“基础”效应物活性。然而，开始出现的证据表明，反向激动剂具有超越简单降低基础效应物活性的新作用，并且这些新作用发生在非突变受体以自然密度表达的系统中。 我们已经发现，即使5-HT 2C反向激动剂不降低表达低水平人5-HT 2C受体的CHO细胞中的基础效应子活性，它们也增强5-HT 2C受体系统和内源性表达的嘌呤能受体系统两者的响应性。 这些数据表明，反向激动剂的细胞作用可能是通过激活受体系统介导的，这些受体系统不是这些药物的直接靶点。 由于许多以前被认为是拮抗剂的治疗和研究药物最近已被证明（或怀疑）是反向激动剂，这些新的行动可能是重要的治疗效果。 为了在生理学相关的模型系统中探索反向激动剂的这些新作用，我们提出：1）检验以下假设：5-HT 2A和5-HT 2C受体在脑中组成性地活性，并且当在细胞培养模型中以自然密度表达时。 此外，我们将检验这些受体系统由于效应子系统的组分的次敏感性而部分脱敏的假设;和2）检验在生理学相关模型系统中配体非依赖性5-HT 2A和5-HT 2C受体活性导致共享相同受体后信号传导组分的其他非靶受体系统的组成性脱敏的假设。 我们将测量5-HT 2A/2C反向激动剂改变对受体活化的反应的能力，所述受体不是5-HT 2A/2C反向激动剂的直接靶点（例如嘌呤能、毒蕈碱能和肾上腺素能受体），但已知其活化相同的细胞效应子途径。 这项研究将提供有关反向激动剂的细胞效应的重要信息，这将有助于我们更好地了解各种治疗和研究药物的作用。

Currently there is considerable interest and debate as to whether inverse agonists represent merely a pharmacological curiosity or whether they have physiologically relevant actions and therapeutic potential. The debate arose because inverse agonism has been demonstrated primarily in artificial systems where receptors are overexpressed or mutated (constitutively active mutants). In these non-natural systems, inverse agonists typically reduce "basal" effector activity as a result of reducing ligand-independent (constitutive) receptor activity. However, evidence is beginning to emerge which suggests that inverse agonists have novel actions that extend beyond simply reducing basal effector activity and that these novel effects occur in systems where non-mutated receptors are expressed at natural densities. We have found that even though 5-HT2C inverse agonists do not reduce basal effector activity in CHO cells expressing low levels of the human 5-HT2C receptor, they enhance the responsiveness of both the 5-HT2C receptor system and the endogeously expressed purinergic receptor system. These data suggest that cellular actions of inverse agonists may be mediated through activation of receptor systems that are not direct targets for these drugs. Since many therapeutic and investigational drugs that were previously thought to be antagonists have recently been demonstrated (or are suspected) to be inverse agonists, these novel actions may be important for their therapeutic efficacy. To explore these novel actions of inverse agonists in physiologically relevant model systems, we propose to: 1) test the hypothesis that 5-HT2A and 5-HT2C receptors are constitutively active in brain and when expressed at natural densities in cell culture models. Further, we will test the hypothesis that these receptor systems are partially desensitized due to subsensitivity of components of the effector system; and 2) test the hypothesis that ligand-independent 5-HT2A and 5-HT2C receptor activity, in physiologically relevant model systems, leads to constitutive desensitization of other non- target receptor systems that share the same post-receptor signaling components. We will measure the capacity of 5-HT2A/2C inverse agonists to alter responses to activation of receptors which are not direct targets for 5-HT2A/2C inverse agonists (e.g. purinergic, muscarinic, and adrenergic receptors), but which are known to activate the same cellular effector pathways. This study will provide important information about the cellular effects of inverse agonists which should help us to better understand the actions of a variety of therapeutic and investigational drugs.