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

最近发现的多巴胺能和多巴胺能之间的联系 系统提出了一种控制相关问题的新方法 使用和滥用成瘾性和精神改变药物。一个主要 谷氨酸受体亚型是一种超分子复合物， N-甲基-D-天冬氨酸（NMDA）受体以及 甘氨酸、镁、锌、含有识别位点的阳离子通道 开放通道阻滞剂如苯环己哌啶（PCP）和聚胺 研究中心。已经表明，竞争性和非竞争性NMDA 拮抗剂在耐受性的发展中发挥控制作用， 依赖，阿片类药物，并能够减轻戒断 行为。具体而言，竞争性作用于NMDA的化合物 结合位点，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位点，已被发现， 有效不幸的是，所有上述遭受的副作用， 使其不能长期使用。一类非竞争性NMDA 在本文中尚未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 已经鉴定了拮抗剂，通过多胺位点的控制可以 提出了一个有用的方法。该提案旨在确定 分子参数负责多胺的效力和功效. NMDA受体。为此，我们将进行系统的 多胺类似物的研究，其中个别参数， 分子构象、碱性、氢键和空间因子 会有所不同。这些参数与效价的相关性， 在NMDA受体的功效将导致高度的发展 有效的，特异性拮抗剂，可用于控制 耐受性、依赖性、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.