Design and development of 5-HT7 receptor agonists

描述（由申请人提供）：对5-HT7受体的兴趣主要来自于它们在正常或受损记忆中发挥相关作用的可能性。大量研究发现，在海马形成（HF）和额叶皮层的认知通路中存在5-HT7受体的证据。众所周知，在衰老或阿尔茨海默病（AD）期间，5-HT7受体似乎在raphe复合体中下降。5-HT7受体拮抗剂SB-269970 （5-HT7受体拮抗剂）可增强记忆巩固，减弱mRNA受体表达，并逆转5-HT7受体的促进记忆作用，这也证实了5-HT7受体参与记忆机制的证据。了解5-HT7受体在认知过程中的作用，包括学习和记忆，受到缺乏高选择性激动剂的限制。该项目的中心假设是芳基哌嗪、硫代吡啶和2-苯胺咪唑啉类似物的激动剂配体在与5-HT7受体相互作用时以类似的方式结合，并利用受体激动剂活性所需的一些常见乙胺侧链构象。本研究的主要目标是开发一系列构象受限的吡啶和硫代吡啶类似物，并将其作为设计和开发强效、高选择性5-HT7受体激动剂的模板。这些模板来源于对四种主要的选择性和非选择性5-HT7受体激动剂的比较分析：芳基哌嗪、氨基四联蛋白/铬、硫代吡啶和2-苯胺咪唑。所提出的模板中取代基的性质和位置也可以为我们提供多种新的5-HT7受体激动剂。本申请的具体目的如下：(i)基于含有共同结构元素的模板制备一系列构象受限的吡啶和硫代吡啶类似物作为潜在激动剂；（ii）首先确定它们与5-HT7受体的结合谱，然后研究它们与5-HT1A、5-HT2A、D2L、¿1和¿2肾上腺素受体的亲和力，以确定选择性；（iii）确定拟议结构在5-HT7受体上的内在活性，除了那些对5-HT7受体没有亲和力的结构；（iv）利用所提出的模板和获得的药理学结果来确定5-HT7受体的选择性和激动剂活性所必需的关键结构元件。拟议研究的结果将作为另一个长期项目的初步数据。该项目的目标将包括：(i)发展5-HT7受体激动剂的结构-亲和关系（SAFIR）和结构-活性关系（SAR）， （ii）阐明5-HT7受体及其激动剂在记忆障碍病因学中的功能，以及（iii）设计和开发可能用于治疗老年相关衰退和AD的功能障碍记忆的有效药物。

DESCRIPTION (provided by applicant): Interest in 5-HT7 receptors derives mainly from the possibility that they can play a relevant role in normal or impaired memory. Numerous studies have found evidence of the presence of 5-HT7 receptors in cognitive pathways within hippocampal formation (HF) and the frontal cortex. It is known that 5-HT7 receptors appear to decline in the raphe complex during aging or Alzheimer's disease (AD). The evidence for the involvement of 5-HT7 receptors in mnemonic mechanisms was also confirmed by findings showing that the potential selective 5-HT7 receptor agonist AS 19 enhanced memory consolidation, attenuated mRNA receptors expression, and the facilitatory memory effect was reversed by SB-269970 (5-HT7 receptor antagonist). Understanding the role of 5-HT7 receptors in cognitive processes, including learning and memory, is limited by the lack of highly selective agonists. The central hypothesis of the proposed project is that the agonist ligands of arylpiperazine, thiopyridine and 2-anilinoimidazoline analogs bind in a similar manner upon interaction with 5-HT7 receptors and utilize some common ethylamine side-chain conformation required for agonist activity at the receptor. The major goal of the proposed research is to exploit a series of conformationally restricted pyridine and thiopyridine analogs, and to use them as templates for the design and development of potent and highly selective 5-HT7 receptor agonists. These templates are derived from a comparable analysis of four major classes of selective and nonselective 5-HT7 receptor agonists: arylpiperazines, aminotetralins/chromans, thiopyridines, and 2-anilinoimidazolines. The nature and position of substituents in the proposed templates can also provide us with a diversity of new 5-HT7 receptor agonists. The specific aims of this application are as follows: (i) prepare a series of conformationally restricted pyridie and thiopyridine analogs as potential agonists based on the templates containing common structural elements; (ii) determine their binding profile initially at 5-HT7 receptors and then stuy their affinity at 5-HT1A, 5-HT2A, D2L, ¿1, and ¿2 adrenoceptors to determine selectivity; (iii) determine the intrinsic activity of the proposed structures at 5-HT7 receptors, except for those that will have no affinity at 5-HT7 receptors; (iv) utilize the proposed templates and obtained pharmacological results to identify key structural elements essential for selectivity and agonist activity for 5-HT7 receptors. The findings of the proposed studies will serve as preliminary data for a further long-term project. The aim of the project will include: (i) development of the structure-affinity relationships (SAFIR) and structure-activity relationships (SAR) of the 5-HT7 receptor agonists, (ii) clarification of the function of 5-HT7 receptors and their agonists in the etiology of memory disorders, and (iii) design and development of potent agents that may find therapeutic application for the treatment of dysfunctional memory in aged-related decline and AD.