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

The problem is to rationally design pharmaceutical drugs that are safer and more clinically effective. Previous attempts to design new drugs required the design of new molecules. This meant that a single molecule had to possess all of the desired properties, but little or none of the unwanted side-effects for a successful pharmaceutical product. This paradigm has served the pharmaceutical community for over fifty years. However, as previously known in chemistry, the fact that buffers are useful discoveries that combine an acid and base plus their conjugate salts, this has begun to take hold in pharmacology as combination products have increased due to their superior or synergistic effects. Many times the effects of either a chemical or pharmaceutical combination will be different than the effects from either molecule of the combination alone. This new paradigm suggests that older drugs may be altered and perhaps improved by combining them in novel ways.

The basic research behind the work to explore these ideas was begun with the underlying philosophy that accurate biophysical descriptions of drug-receptor interactions will lead to safer and better pharmaceuticals. One of the perils of drug development is the occurrence of desensitization, also denoted as tachyphylaxis, autoinhibition, fade, tolerance or down-regulation. Many in the industry believe that by selecting the proper dosage regime drug-receptor desensitization can be minimized or prevented. Rightly or wrongly, this practice creates a tightrope between a therapeutic or desensitizing dose that patients and doctors must walk when utilizing medications that desensitize their target receptors. This may affect anywhere from thirty to fifty percent of all pharmaceuticals and be a fertile area for drug development and improvement in the future.

Our approach is based upon basic research that provides for an improved scientific understanding of receptor desensitization and for a method to inhibit desensitization at the receptor level (USP 6,593,094; USP 6,673,558 and Intl. J. Pharmacol. 1(2): 122-131, 2005). This may lead to a potentially safer class of drugs with better therapeutic effects. Predictions from this work suggested that by using specific agonist/antagonist combinations (Optimal Ratio Combinations - ORCs) receptor desensitization could be prevented. This was tested and found to be valid for three different tests of the model for three different agonists in two different systems.

This work also provides a better scientific understanding to control receptor desensitization by optimizing agonist/antagonist combinations. This may create new ways to design safer and more effective drugs in a number of important therapeutic areas that could lead to a new class of drug combinations. This technology is now available for licensing. Those with a vision for a future with safer, more effective drugs will commit to the scientific development of combination pharmaceuticals with superior characteristics compared to single molecular entities alone.

Richard Lanzara, Ph.D.
President
Bio Balance, Inc.

Bio Balance ( http://www.bio-balance.com/ ) is an early stage drug development company that has developed the only tested method to prevent drug desensitization at the receptor level. This phenomenon, also known as down-regulation, tolerance or fade, occurs with a large number of very commonly used drugs such as dobutamine for heart failure, isoproterenol for shock or asthma, L-dopa for Parkinson’s Disease, and morphine for pain. Notably, desensitization cannot be remedied by taking larger dosages. With more and more drug, efficacy diminishes and the drug essentially stops working. By using a patented approach, we create new, combination drug candidates that sustain the therapeutic response with a better side-effects profile than the original drugs.