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.
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