DEVELOPMENT OF P2 RECEPTOR LIGANDS

P2核苷酸受体的至少14种亚型的克隆给药物化学家提出了一个独特的挑战：为这种多样性的受体设计选择性激动剂和拮抗剂，而现有的线索很少。这些受体调节中枢神经系统、免疫系统、心血管系统和平滑肌的功能。我们的实验室正在开发这些受体的选择性激动剂和拮抗剂，用作探测受体功能的药物工具和潜在的治疗剂。P2 X受体是配体门控离子通道。P2 Y受体是作为第二信使与磷脂酰肌醇途径连接的G蛋白偶联受体。作为P2 Y家族的代谢型嘌呤和嘧啶核苷酸受体的代表的人P2 Y1受体可以基于视紫红质模板进行建模，并且所得模型与药理学和诱变结果高度一致。已确定跨膜和细胞外结构域中的带电残基以及受体活化所必需的两个二硫桥。选择性P2 Y1受体拮抗剂，如腺嘌呤核苷酸MRS 2179（N-甲基-2？脱氧腺苷-3？，五个？二磷酸盐）及其碳环类似物正在开发中。P2 X受体的建模尚未实现，因为不存在细胞外核苷酸结合区的模板。然而，已经鉴定了该亚型的选择性拮抗剂MRS 2220和增效剂MRS 2219。两者都是基于结构吡哆醛-5？-磷酸盐拮抗剂（如PPADS），正在检查所有P2受体亚型的SAR。- 核苷酸、离子通道、G蛋白偶联受体、激动剂、拮抗剂、有机化学、受体药理学

The cloning of at least fourteen subtypes of P2 nucleotide receptors has presented a unique challenge to medicinal chemists: the design of selective agonists and antagonists for this multiplicity of receptors with few existing leads. These receptors regulate function of the central nervous system, the immune system, the cardiovascular system, and smooth muscles. Our laboratory is developing selective agonists and antagonists for these receptors, for use both as pharmcological tools for probing receptor function and as potential therapeutic agents. P2X receptors are ligand-gated ion channels. P2Y receptors are G protein coupled receptors linked to the phosphatidyl inositol pathway as second messenger. The human P2Y1 receptor as representative of the P2Y family of metabotropic purine and pyrimidine nucleotide receptors may be modeled based on a rhodopsin template, and the resulting model is highly consistent with pharmacological and mutagenesis results. Charged residues in both the transmembrane and extracellular domains and two disulfide bridges essential for receptor activation have been identified. Selective P2Y1 receptor antagonists such as the adenine nucleotide MRS 2179 (N-methyl-2?-deoxyadenosine-3?,5?-bisphosphate) and it carbocyclic analogue are under development. Modeling of P2X receptors has not been achieved, since no template for the extracellular nucleotide binding region exists. Nevertheless, a selective antagonist, MRS 2220, and a potentiator, MRS 2219, of this subtype have been identified. Both are based structurally on pyridoxal- 5?-phosphate antagonists (such as PPADS), for which the SAR is being examined at all of the P2 receptor subtypes. - nucleotides, ion channels, G protein coupled receptors, agonists, antagonists, organic chemistry, receptor pharmacology