MEDICATIONS FOR OPIATE WITHDRAWAL AND AIDS DEMENTIA

药物滥用是一个持续存在的问题，同时还伴随着不断扩大的社会 街头暴力增加的代价，犯罪受害者的痛苦，毒品- 与虐待有关的死亡和艾滋病毒感染和艾滋病发病率的增加。 由于毒瘾不是自我治疗的，化学方法结合起来 对于心理治疗，需要后续的监测和咨询。 化学制剂，如美沙酮，一种激动剂，提供了一个可以接受的第一个 在戒毒过程中迈出一步，但之后必须进行治疗 使用纳洛酮或纳曲酮等拮抗剂。因为这些特工领导着 癫痫，快感缺乏，烦躁不安和抑郁，以及其他症状， 吸毒者拒绝接受这一部分的治疗，通常会再次吸毒 虐待。谷氨酸能功能的阻断已被证明可以减弱 由纳洛酮引起的戒断症状，但在N- 甲基-D-天冬氨酸(NMDA)受体或NMDA相关离子内 经络，有多种不良副作用。另一方面， NMDA拮抗剂通过士的宁不敏感的甘氨酸起作用 已发现识别部位可以抑制许多吗啡的迹象 停药不会有有害的副作用。封锁NMDA 神经毒性也被证明可以防止神经元损伤。 由HIV-1感染引起，并与HIV-1相关 认知/运动复合体(艾滋病痴呆)。这项建议的目的是 确定高效拮抗剂的分子需求 NMDA通过其相关的士的宁不敏感的甘氨酸识别 地点。这个问题将通过利用已知的要求来解决 用于甘氨酸位点的高亲和力结合设计和合成 有效的α，β-不饱和α-氨基酸并对它们进行评估 NMDA受体的效力和效力。强大的对手将是 NIDA在猴子单次剂量抑制试验中通过 OTDP。强大的拮抗剂也将被测试以消除神经元 由HIV分泌的外壳蛋白gpl20造成的损害。前景看好的代理商 将测试它们对正常啮齿动物学习和记忆的影响 在艾滋病的啮齿动物模型中。

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.