|
Cigarrete smokers have the nicotine patch, heroin addicts have methodone, and if recent findings are any indication of what's to come, cocaine abusers may soon be able to take a pill in order to help wean them from their dependency. This approach, in which one drug is given to a patient in an attempt to ease them off of another more harmful substance, is known as substitution medication and the prospect of this type of treatment comes none to soon for the thousands of people helplessly hooked on cocaine.
The promising new drug, RTI-76, is one of a class of approximately 400 compounds, each synthesized for the short term purpose of revealing key features about the interaction between cocaine and its receptor, and for the long term goal of developing medications for cocaine abusers. Named for the Research Triangle Institute, the location where medicinal chemist Dr. F. Ivy Carroll has spent the past ten years synthesizing these drugs, the RTI compounds all possess one thing in common with cocaine - they all have the same backbone configuration that cocaine has. That is, the ring of seven carbon atoms which forms the basis of cocaine's structure is present in the hundreds of cocaine analogs as well. What makes each compound unique is the group of elements (substituents) which happen to be attached to one of the seven carbons in the ring. By varying these substituents, one can alter both the chemical and behavioral properties that each drug possesses until eventually a drug is created which fullfills the criteria necessary to be considered a cocaine medication. To date, the studies conducted in rodents at Dr. Michael J. Kuhar's laboratory at Emory University, indicate that RTI-76 may have the potential to be this drug or at the very least, it may be used as a tool for determining the complete biochemical effects of cocaine administration.
Important properties for medications designed to treat cocaine abuse include affinity, specificity, slow entry into the brain, and a long duration of action. The first two characteristics relate to the chemical aspects of an ideal medication. The affinity refers to how attractive a drug is towards its particular receptor site. The greater the affinity, the greater the likelihood that the drug is to be found bound to its particular site. According to Carroll, cocaine ordinarily has an affinity for three sites where our bodies own "naturally" produced drugs, also known as neurotransmitters, typically attach. The three sites to which cocaine binds are the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) sites. When the presence of cocaine is great enough that it prevents the dopamine, serotonin, and norepinephrine neurotransmitters from binding to their respective sites, these drugs cannot be broken down and as a result they accumulate in certain areas of our brain. (It is this accumulation, especially of dopamine, which is believed to be the basis for the euphoric feelings often induced following cocaine administration). Like cocaine, RTI-76 has been shown to have an affinity for DAT, SERT, and NET, though its affinity for NET is not nearly as high as its affinity for the other two transporter sites.
What makes RTI-76 a particularly promising drug is the fact that it has recently been shown to fullfill the second characteristic of an ideal cocaine medication, that of specificity. Specificity refers to whether the binding of a drug to various transporter sites is of a large enough extent that it indiscriminately prevents all neurotransmitters from binding to their sites versus whether the drug prevents only certain neurotransmitters from binding to their sites. Following the completion of numerous binding experiments, Dr. Kuhar's laboratory has detemined that RTI-76 does indeed possess the specificity quality.
In order to successfully conduct the binding experiments to determine specificity, rats were initially treated with either RTI-76 or saline. (The saline treated rats represented the control group and thus served as a basis for comparison with the RTI-76 rats). The cortex of all of the subjects were then treated with a norepinenphrine-like compound (nisoxetine), which ordinarily has a high affinity for NET binding sites. This norepinephrine-like compound was radioactively tagged prior to its addition to the cortex. Therefore the extent to which the nisoxetine bound to the NET could subsequently be counted in both the RTI-76 and saline treated rats. If RTI-76 did indeed bind to NET to a large extent, then it would have prevented the radioactively tagged nisoxetine from binding to the NET, and thus the subsequent number of counts would have been lowered.
The results indicated that the amount of radioactive counts in the cortex of the rats that received the RTI-76 treatment did not differ from the amount of radioactive counts in the cortex of the saline-treated rats. Thus, the presence of RTI-76 did not alter the extent of nisoxetine binding to NET. However, similar binding experiments conducted with radioactively tagged serotonin-like and dopamine-like compounds indicated that RTI-76 did inhibit the amount of binding to SERT and DAT respectivly. Taken together, the results of the binding experiments indicate that when RTI-76 is administered to rats it does not unilaterally block all neurotransmitter from binding to their sites, rather it specifically prevents only the dopamine and serotonin neurotransmitters from binding.
Given the promising results from RTI-76 studies, some may be wondering, "Why isn't this drug being given to cocaine addicts to help ease them from their dependency?". Doing so at this point would be a bit premature since it has not yet been determined whether or not RTI-76 fufills the last two characteristics of an ideal medication, those being slow entry into the brain and long duration of action. The rate at which drugs such as cocaine and cocaine analogs enter the brain plays a critical role in determining the intensity of the euphoria (also known as the "high") felt following administration. The duration of action of the drugs determines how long the euphoria is felt before withdrawal (or the "low") sets in.
When cocaine is injected into the body, it enters the brain very rapidly (within approximately 15 minutes). As a result of cocaine's presence and quick entry, neurotransmitters (especially dopamine) are blocked from their binding sites. They can't subsequently be taken to a different place where they would ordinarily be broken down, and as a result their levels accumulate within the brain. Because of the quickness of cocaine's entry, the neurotransmitter levels rise very fast. It is this fast increase which is thought to account for the intense feelings of well-being commonly associated with cocaine. Although cocaine has a fast rate of entry, it's duration of action is quite short. Within 2 hours following injection, neurotransmitters return to their normal levels and the intense euphoric feelings are gone. At this point one would be going through withdrawal. In order for RTI-76 to be used as a cocaine medication, its rate of entry into the brain would have to be slower (on the order of 2 hours), and its duration of action would have to be longer (approximately 8 hours) than that of cocaine. In this way, though the intensity of the "high" felt by the patients would not be as great, the period of time over which it would last would be much longer.
One final practical note with regard to RTI-76 and duration of action. If the duration of action of RTI-76 were short, then one would have to take numerous pills a day, rather than say two or three, in order to prolong the "high" for an extended period of time. This may lower the percent of compliance among the patients, and hence reduce the effectiveness of using RTI-76 to treat cocaine addiction.
Unfortunately, cocaine abuse is a significant social and health problem in the United States today. Merely a few years ago, the idea of cocaine addicts being able to help themselves by taking a drug such as RTI-76, was something that many would have thought impossible. Now, this idea does not seem so far-fetched, and if research on RTI-76 continues to yield promising results, this idea may become a reality - making cocaine addiction a thing of the past.
|
