MEDICATIONS FOR OPIATE WITHDRAWAL AND AIDS DEMENTIA

药物滥用是一个持续存在的问题， 街头暴力增加的代价，犯罪受害者的痛苦，毒品， 与虐待有关的死亡以及艾滋病毒感染和艾滋病发病率的增加。 由于药物成瘾是不能自我治疗的，化学方法，结合 心理治疗，后续监测和咨询，是必需的。 化学药剂，如美沙酮，激动剂，提供了一个可接受的第一 这是停药过程中的一步，但必须随后进行治疗 与拮抗剂如纳洛酮或纳洛酮联用。既然这些探员 癫痫、快感缺乏、烦躁不安和抑郁等症状， 瘾君子拒绝接受这部分治疗，通常会重新吸毒。 虐待已经证明阻断多巴胺能功能可以减弱 戒断症状沉淀纳洛酮，但代理人在N- 甲基-D-天冬氨酸（NMDA）受体或NMDA相关离子内 通道，有各种不良的副作用。另一方面，在一项研究中， 通过士的宁不敏感的甘氨酸起作用的NMDA拮抗剂 已经发现识别位点抑制吗啡的许多迹象 戒断而无有害副作用。封锁NMDA 神经毒性也被证明可以防止神经元损伤 导致HIV-1感染，并负责HIV-1相关 认知/运动复合体（艾滋病痴呆）。这一建议旨在 确定高效拮抗剂的分子要求， NMDA，通过其相关的士的宁不敏感的甘氨酸识别 绝佳的价钱这个问题将通过利用已知的需求来解决 用于在甘氨酸位点处的高亲和力结合以设计和合成 有效的α，β-不饱和α-氨基酸，并评估它们的 对NMDA受体的效力和功效。有效的拮抗剂将是 通过NIDA在猴“单次给药抑制试验”中评价， OTDP。还将测试有效的拮抗剂对神经元细胞凋亡的消除。 由HIV分泌的外壳蛋白gp 120引起的损伤。有前途的代理商 将测试它们对正常啮齿动物学习和记忆的影响 以及啮齿类动物的艾滋病模型。

Drug abuse is a continuing problem which is coupled with expanding social costs of increased street violence, suffering of victims of crime, drug- abuse related deaths and increased incidence of HIV infection and AIDS. Since drug addiction is not self-treatable, chemical approaches, combined with psychotherapy, follow-up monitoring and counseling, are required. Chemical agents such as methadone, an agonist, provide an acceptable first step in the drug withdrawal process, but must be followed by treatment with antagonists such as naloxone or naltrexone. Since these agents lead to seizures, anhedonia, dysphoria and depression, among other symptoms, addicts refuse this part of the treatment, and usually relapse into drug abuse. Blockade of glutamatergic function has been shown to attenuate the withdrawal symptoms precipitated by naloxone, but agents acting at the N- methyl-D-aspartate (NMDA) receptor or within the NMDA-associated ion channel, have a variety of undesirable side-effects. On the other hand, NMDA antagonists operating via the strychnine-insensitive glycine recognition site have been found to suppress many of the signs of morphine withdrawal without deleterious side-effects. Blockade of NMDA neurotoxicity has also been demonstrated to prevent neuronal damage resulting from HIV-1 infection and responsible for HIV-1 associated cognitive/motor complex (AIDS dementia). This proposal is aimed at identifying the molecular requirements for high potency antagonists of NMDA , through its associated strychnine-insensitive glycine recognition site. The problem will be addressed by utilizing the known requirements for high affinity binding at the glycine site to design and synthesize potent alpha, beta-unsaturated alpha-amino acids and evaluate them for potency and efficacy at the NMDA receptor. Potent antagonists will be evaluated by NIDA in the monkey "single dose suppression test" through the OTDP. Potent antagonists will also be tested for abrogation of neuronal damage caused by the HIV secreted coat protein, gpl20. Promising agents will be tested for their effects on learning and memory in normal rodents and in rodent models of AIDS.