SAR OF THE POLYAMINE SITE(S) AT THE NMDA RECEPTOR

最近发现的多巴胺能和谷氨酸能之间的联系 系统提出了一种控制相关问题的新方法 使用和滥用令人上瘾和改变精神的药物。一位少校 谷氨酸受体是谷氨酸的一种亚型，它是一种超分子复合体 N-甲基-D-天冬氨酸(NMDA)受体及其离散结合部位 甘氨酸、镁、锌，一种含有识别位点的阳离子通道 适用于开放通道阻滞剂，如苯环利定(PCP)和多胺 网站(S)。已有研究表明，竞争性和非竞争性NMDA 拮抗剂在耐受性的发展过程中发挥控制作用 对鸦片类药物的依赖，并能够减轻戒断 行为。具体地说，在NMDA发挥竞争作用的化合物 结合部位，以及非竞争性通道阻滞剂和拮抗剂 作用于士的宁不敏感的甘氨酸部位，已被发现 有效。不幸的是，所有这些都有副作用， 使其不能长期使用。一类非竞争性NMDA 在这方面尚未被探索的拮抗剂是多胺。 由于多胺激动剂、部分激动剂、反向激动剂和 已鉴定出拮抗剂，通过多胺部位进行控制可 提出一种有用的方法。这项建议旨在确定 影响多胺的效力和功效的分子参数 NMDA受体。为此，我们将开展系统的 研究多胺类似物中的个别参数，如 分子构象、碱度、氢键和空间因子 将是多种多样的。这些参数与电势和电势的相关性 NMDA受体的有效作用将导致高度 有效的、特定的拮抗剂，可能有助于控制 耐受、依赖、药物成瘾和戒断的发展 行为。

The recently identified link between the dopaminergic and glutamatergic systems suggests a novel approach to the control of problems associated with the use and abuse of addictive and mind altering drugs. A major subtype of glutamate, receptor is the supramolecular complex containing an N-methyl-D-aspartate (NMDA) receptor as well as discrete binding sites for glycine, magnesium, zinc, a cation channel containing recognition sites for open channel blockers such as phencyclidine (PCP) and polyamine site(s). It has been shown that competitive and noncompetitive NMDA antagonists exert control in the development of tolerance to, and dependence on, opiates, and are capable of attenuating withdrawal behaviors. Specifically, compounds acting competitively at the NMDA binding site, as well as noncompetitive channel blockers and antagonists acting at the strychnine-insensitive glycine site, have been found to he effective. Unfortunately, all the above suffer from side-effects which make them unacceptable for long-term use. A class of noncompetitive NMDA antagonists which has not been explored in this context is the polyamines. Since polyamine agonists, partial agonists, inverse agonists and antagonists have been identified, control via the polyamine site may present a useful approach. This proposal is aimed at determining the molecular parameters responsible for potency and efficacy of polyamines at the NMDA receptor. To this end we will carry out a systematic investigation of polyamine analogs in which individual parameters such as molecular conformations, basicity, hydrogen bonding and steric factors will be varied. Correlation of these parameters with the potencies and efficacies at the NMDA receptor will lead to the development of highly potent, specific antagonists which could be useful in controlling development of tolerance, dependence, drug addiction and withdrawal behaviors.