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.
|Lewin, A H; Sun, G; Fudala, L et al. (1998) Molecular features associated with polyamine modulation of NMDA receptors. J Med Chem 41:988-95|