New Agonist/Antagonist Optimal Ratio Combinations as a Potentially Safer Class of Pharmaceutical Drugs


Why Aren't Drugs Safer? - Is It Because We Need A Fundamental Understanding of the Receptor Response?


In order to create safer pharmaceutical drugs, we need a fundamental understanding of the receptor response. What does this mean? Basically we'd like to know how drugs activate or deactivate their target receptors. This sounds simple enough, yet with all of the research time and money that's been thrown at this problem we still don't have agreement on the underlying biophysical mechanism for receptor activation or response. Perhaps this partially explains why we miss some of the serious side effects of drugs.


Scientifically accurate descriptions of drug-receptor interactions should eventually lead to better pharmaceuticals; therefore, this should be a top priority for future pharmaceutical research. In this age of computers, one would think that computer models would provide us with straightforward explanations for the receptor response. Why hasn't this happened during the past few decades of intense research?


Surprisingly, not even the most modern computers are up to the task. This is due to problems that include inadequate descriptions of the basic biophysical picture and the inexact nature of our computer simulations. Also as many computer models become increasingly complex, we lose the ability to "see" what is happening at the level required for us to truly understand the underlying mechanism. Although our computers provide us with large amounts of output, the complexity of the computer code requires us to interpret the output in meaningful ways. This is big business in pharmaceutical and academic research today.


However, in the face of sometimes daunting scientific challenges, it is often prudent to limit one's efforts to those parts of the picture that are amenable to our computational simulations. This, however, may limit us to only incremental progress. As scientists, we all like to believe that we're contributing meaningful work toward solving particular problems. However, we know that we must be missing key concepts that prevent a true breakthrough in our understanding of the receptor response. On the other hand, there sometimes occurs a new concept that's just so outrageous that it might be enough to provide the breakthrough we need. This has certainly happened before in the history of science with the caveat that a new concept usually isn't accepted quickly because most scientists don't have enough time, energy, or motivation to check it.


With that warning, the fundamental concept that prevents us from understanding receptor response is how we define a relatively simple chemical concept called an equilibrium. This may seem far removed from the study of biological receptors or even foolish because the concept of chemical equilibrium seems so firmly established, but it lies at the very core of the problem to model the receptors' behavior because it is the perturbation of the equilibrium of the receptor that determines the response.


The problem is that the true chemical equilibrium is composed of multiple microstates interacting with many other microstates of many other molecules in solution. A microstate is a detailed configuration of a molecular system that includes specific molecular conformations and interactions. The reality is that even with our most sophisticated computers we can't account for all of the microstates comprising a particular concentration within an equilibrium. To do this we would have to calculate all of the different pH-dependent states interacting with the various counterion binding states, which are an excessively large number of possible combinations for modeling any proteins or receptors in solution. Therefore, in our attempt to model molecular and chemical behavior, we lump these microstates together into one state that we label a concentration.


Although these molecular microstates are far too numerous to model, if one can discover a suitable receptor model with a feasible biophysical mechanism for a two-state receptor system, then one can test the predictions of such a model using various computational simulations. These two-state systems also represent an obvious simplification of the underlying microstates. However, over the years they have been useful in describing drug-receptor systems in an on-off fashion and have recently made something of a comeback in pharmacology theory.


For a simple two-state receptor system with a binding molecule that reacts differently with either side of a two-state equilibrium, there will be a stress created on the side of the equilibrium that reacts the most with the binding molecule. This requires a compensatory shift toward the more active side of the equilibrium to relieve this stress. This shift has been known in chemistry for many decades as Le Chatelier's principle. As strange as it may seem, we can make an analogy between the poised chemical equilibrium of a receptor in either of two states and a weighing on a simple beam balance. This allows us to see that the chemical equilibrium is very similar to the behavior of a simple balance.


The reason has to do with the underlying changes within the microstates comprising the chemical equilibrium that increase the probability of a receptor molecule being on one side of the equilibrium or the other (e.g. in a simple two-state system). This is analogous to the addition of weights to either side of a physical balance causing the balance to tip toward the more weighted side. By altering the probabilities of the underlying receptor microstates, the chemical equilibrium shifts and thereby represents something more than the simple concentration expressions. Instead the shift represents a change in the underlying probability distribution of microstates for the chemical concentrations.


The mathematical calculation for this shift requires that a ratio of states be constructed for two equal processes. The calculation is the same for a simple balance where a displacement may be obtained by either the addition of unequal weight to either side or by the transfer of weight from one side of the balance to the other. Combining the equivalent changes creates a fundamental equation for equilibrium that allows us to solve for the initial shift.


One of the most fascinating observations from this approach is that the solution for this initial shift obeys a fundamental psychophysical law called Weber's law or the Weber-Fechner law (see - Weber's Law Modeled by the Mathematical Description of a Beam Balance, Mathematical Biosciences 122: 89-94 (1994)). Our sensory systems that depend on cellular receptors also obey this law.  Why would a simple balance obey a law that also applies to our sensory perceptions? This observation links the chemical equilibrium of receptors with the equilibrium of a simple balance and further suggests a common mechanism between the physical, chemical, biological and physiological realms. The mechanism is that the perturbation of a two-state equilibrium that alters the underlying probabilities makes one side of the equilibrium more or less likely than the other side.


In pharmacology, this perturbation or shift was never before calculated as a separate parameter and examined to see whether or not it describes the drug-receptor response until a little more than thirteen years ago when the theory was first conceived (see - A Method for determining drug compositions to prevent desensitization of cellular receptors. U.S. Pat. 5,597,699 (1997) - note that this patent was originally begun in 1992). Since then it has been tested a number of times both in vivo and in vitro and found to be a valid predictor of receptor response (see the most recent results in - Optimal Agonist/Antagonist Combinations Maintain Receptor Response by Preventing Rapid Beta-1 adrenergic Receptor Desensitization Intl. J. Pharmacol., 1(2): 122-131, 2005 and for the derivation).


We now understand that receptors function as poised chemical balances that can be shifted to either side by unequal ligand binding. However, one of the more difficult concepts is to explain how receptors desensitize. This means that the receptor's response decreases in the continued presence of a stimulus. This seems to be counterintuitive, but it affects anywhere from thirty to fifty percent of all drug receptors and can occur rapidly within milliseconds to minutes. Wouldn't it be fascinating if the simple balance also desensitized?  In fact, the balance also desensitizes just like the biological receptors if the weights are distributed by a Langmuir binding expression, which is a fundamental chemical expression for calculating molecular binding (see -  Desensitization of a balance with Langmuir binding of weights. arXiv 2003, Perhaps this finding is expected if the chemical balance is being influenced by the physical binding of the ligands, but it nevertheless seems extraordinary that such a relatively simple physical system can model some of the most intractable, nonlinear problems of biological modeling.


Understanding these concepts with such a simple model, gives us pause to marvel at the fact that we are allowed to understand such things.  We wonder whether this research might also apply to other mathematical, physical, chemical and biological areas and hope that these applications will lead to the development of safer pharmaceutical drugs.


Richard Lanzara, Ph.D.

President and Principal Scientific Officer

Bio Balance, Inc.


Keywords: GPCRs, Adrenergic, receptor model, biophysical model, computational model, two-state model, cysteine, sulfhydryl, thiol, molecular model, acid-base model, mathematical model, nonlinear, probalistic, drugs, biotech, pharmacology, pharmaceuticals, receptor activation.