As reviewed above, the drugs that have been used for their stimulant properties were largely the result of compounds that were discovered empirically over many centuries. Understanding the active principles of these drugs has led to major advances in medicinal chemistry. For example, one of the most exciting recent findings has to do with understand ing the monoamine transporters at the molecular level. Whereas it has been known in pharmacology for many years that cocaine targeted an energy-dependent reuptake pump, the cloning and expression of these transporters has given access to high "purity" proteins that are amenable to more detailed study. These proteins have all been sequenced, and shown to be membrane bound with 12 membrane-spanning helical segments. a large number of site-specific mutations have been used to correlate specific residues in the protein with specific functions. Nevertheless, it will likely take a technical breakthrough to obtain a crystal structure of one of these transporters or one of their homologs, an accomplishment that will no doubt lead to much greater understanding of how transporters function. Inability to crystallize these proteins is not a problem that is unique to monoamine transporters, but continues to plague the study of all membrane-bound transporters and receptors, and other membrane-bound proteins.
Site-directed mutagenesis, cysteine-scan-ning accessibility methods, high field NMR, homology modeling, and continued development of structure-activity relationships will no doubt lead to better and better models of the monoamine transporters. These approaches are having the greatest impact on studies of uptake inhibitors, rather than studies of substrates.
Particularly interesting recent advances indicate that ligands from different chemical classes may bind in novel ways to the dopamine transporter. Using site-directed mutagenesis and photoaffinity labeling probes, investigators have produced results suggesting that the substrate uptake and cocaine binding sites are probably not identical (184). Indeed, it also now seems likely that different chemical classes of uptake inhibitors may even bind to distinct regions of the transporter (185,186), leading to different overall conformations in the transporter protein and perhaps subtly altered mechanisms of inhibition. These different transporter conformations would explain the observed differences in the pharmacology of different chemical classes of DAT inhibitors. New derivatives that have selective affinity at these alternate binding sites may block the actions of cocaine without markedly affecting the normal transport function of the protein. Hence, there is presently intense interest in such compounds because they may provide new avenues for the treatment of cocaine and psychostimulant addiction.
There also is a need for improved drugs to replace existing CNS stimulants, as treatments for medical conditions like narcolepsy, ADHD, obesity, and for general attentional purposes. Yet, virtually all of the existing stimulants have the capacity to produce enhanced mood, or euphoria. This side effect means that they all possess abuse potential to a greater or lesser degree. Advances in medicinal chemistry and molecular neurobiology have provided hope, however, for new generations of drugs. For example, recently the non-amphetamine, nonstimulant drug modafinil (Provigil, 45) was approved for use in narcolepsy (see, e.g., Ref. 187). This drug has been shown to be more effective than amphetamine, with fewer side effects, although its mechanism of action has not yet been elucidated. The discovery that mutations of either the gene for the novel neuromodulator orexin, or the orexin receptor, can cause narcolepsy, leads to the hope for even better and more specific drugs to treat that disorder, as well as to the possibility of better treatments for obesity (188-191).
Even those actions of the stimulants that are absolutely dependent on activation of monoamine systems may also be amenable to breakthroughs in medicinal chemistry. For example, the beneficial effects of stimulants on ADHD may be attributable primarily to activation of only certain receptors. Recently, the anatomical and functional substrates of attention, learning, and memory have begun to yield their secrets. This work has suggested that certain drugs [e.g., selective Dx dopamine agonists (192,193)] may provide all or much of the beneficial effects of the stimulants without the abuse potential. Finally, the cracking of the human genome, and the prediction of more than 100,000 human proteins, offers the hope for novel targets for future efforts in medicinal chemistry. Whereas these may be known neurotransmitter pathways (e.g., GABA or glutamate receptors), new targets may be novel proteins whose function is not understood today, but will be tomorrow, and current uses of psychostimulants may be no more than historical artifacts in a decade.
6.1 Web Site Addresses and Recommended Reading
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