Complexities in Understanding Our Receptors and How We View the Universe...

Previously I mentioned that there exists a devilish complexity in the vast array of chemical and biological modifications that can alter the free thiol or sulfhydryl group, which is the reactive group of the essential amino acid, cysteine, in many important biological proteins (http://ombamltine.blogspot.com/2008/05/devilish-complexity-of-cysteine.html). Thiol groups are vitally important for their ability to form disulfide bonds with other thiol groups and to form either reduced or oxidized (redox) forms as well as oscillating between acid and base states (http://ombamltine.blogspot.com/2008/05/beta-adrenergic-receptor-in-two.html). Any one of these forms may further interact reversibly or irreversibly with a panoply of other chemical and biological molecules. Since most all of the G protein-coupled receptors (GPCRs) that have been studied have thiol (http://ombamltine.blogspot.com/2008/07/evidence-for-free-thiol-necessary-for.html) or disulfide (two thiols linked together) groups, this creates a very complicated picture to understand these receptors’ active and inactive states (http://ombamltine.blogspot.com/2008/08/active-and-inactive-receptor-states.html). This is important in order not only to understand how these receptors work, but to understand how we sense reality (http://ombamltine.blogspot.com/2009/06/how-we-sense-reality-no-really.html) since our sensory receptors are GPCRs. These are also the receptors that are targets of over fifty percent of our pharmaceutical drugs. Understanding how our receptors work at the molecular level is an awe inspiring undertaking, because these are the molecules that link our thoughts and senses to the universe. Understanding how they function may open new frontiers for us to truly understand our place in the cosmos.

My Twitter Mini Review of Pharmacology

Perhaps I need to write the story of how receptors work on Twitter? Humm, which hashtag(s) to use? - #receptor #pharmacology #science

Work at the turn of the last century summarized at - http://ow.ly/R8Hl led to the lock & key concept #receptor #pharmacology #science

Here's a modern version of the "lock and key concept" for the receptor response - http://ow.ly/R8KN #receptor #pharmacology #science

One problem is how does the binding of a small molecule alter the conformation of a much larger one? #receptor #pharmacology #science

Another problem is how do some binding molecules produce a partial or no response? #receptor #pharmacology #science

These problems & desensitization, fade or tachyphylaxis led to the two state theory - http://ow.ly/R8VQ #receptor #pharmacology

Two state mathematics only solved for the fractional or proportional change - http://ow.ly/R91A #receptor #pharmacology #science

Experiments showing an increased response with increased receptor expression didn't fit with 2 state theory #receptor #pharmacology #science

Also no consensus on what the two states of the receptor are -just active & inactive? #receptor #pharmacology #science

I suggested an alternative math to remove these problems with 2 state theory - http://ow.ly/R9jj #receptor #pharmacology #science

The idea was that the net shift could explain a binding molecule's preference - http://ow.ly/R9qX #receptor #pharmacology #science

The "net shift" (delta RH) could fit many classical dose-response curves - http://ow.ly/R9tj #receptor #pharmacology #science

We proposed that a free thiol produced the 2 (acid-base) receptor states - http://cogprints.org/4095/ #receptor #pharmacology

This was a mechanistic hypothesis of receptor function involving sulfhydryl modulation and redox regulation #receptor #pharmacology #science

This also fit nicely with the "net shift" producing the active state of the receptor #receptor #pharmacology #science

Subsequent work seems to support our observations - http://ow.ly/R9PR #receptor #pharmacology #science

Although much more work remains, it looks promising that a free thiol may explain many receptor responses #receptor #pharmacology #science

receptor activation thiol OR sulfhydryl "two state" - http://ow.ly/R9WI #receptor #pharmacology #science

@davidperrey Never seen a review by Twitter before! @rlanzara is trying it using these hashtags - check it out: #receptor #pharmacology #science

For my very mini (and biased) review of pharmacology - http://ow.ly/Rab6 #receptor #pharmacology #science

Bio Balance - Reference Library - http://www.bio-balance.com/Ref.htm

Active and Inactive Receptor States

When we write the set of brackets around a chemical species to represent a chemical concentration, it really represents a sum of probable chemical species that are grouped together. This is especially important when we consider the potential states of large protein molecules such as cellular receptors. In pharmacologic theory, we often characterize the active or inactive states of the receptor as initial quantities such as [R] and [R*]. This is convenient for mathematically manipulating these receptor states in order to derive information about how they behave in the presence of stimulating or inhibiting molecules such as agonists or antagonists, but conveys little about the underlying molecular species connected with these active and inactive states.

Even using specific and detailed molecular dynamic simulations, the meaning behind the [R] and [R*] receptor states becomes less clear when we explicitly model these states. Since there are a vast multitude of possible conformations, it becomes increasingly difficult to separate out those conformations that belong to the active or inactive receptor states. Ironically, this has brought us full circle to consider what [R] and [R*] represent as specific molecular species. The closer we are to understanding the details of these states from crystallographic structures, the further we are from understanding the molecular species that make up the active and inactive states.

Anyone who has truly studied pharmacologic theory and molecular modeling knows that we often wind up with this essential conundrum. Some have chosen particular molecular motions or interactions such as the breaking of a salt bridge or the twist or turn of a helix to describe what they think is the active receptor state. These descriptions may contain accurate descriptions of the active receptor state, but the fact that receptors exist in a sea of thermal noise and that activating drugs or ligands bind to their target receptors with only a 3-4 kcal/mol maximum energy difference and display different active molecular conformations suggest that we need a clearer on and off molecular switch for receptor activation.

These are not impossible physical constraints to accommodate in a biophysical molecular model for receptor activation (see - http://www.bio-balance.com/JMGM_article.pdf and http://www.bio-balance.com/GPCR_Activation.pdf ), but because receptors are complex molecular structures that exist in multiple domains, the teasing apart of the essential molecular signal is very difficult from both an experimental and theoretical perspective. This is particularly true if the biophysical models fail to accommodate major experimental findings such as the redox sensitivity of receptor systems or the reduction in desensitization by combining an antagonist with an agonist. A comprehensive molecular model for receptor activation should contain these findings.

Enhanced Pharmaceuticals, GPCRs, Drug Safety

At Enhanced Pharmaceuticals, we’ve discovered that the rather simple act of combining an agonist with the proper amount of an antagonist allows for a general decrease in the observed drug-receptor desensitization, tachyphylaxis or tolerance. This modulation of the receptor response appears to be a quite general phenomenon applicable to many G Protein-Coupled Receptors (GPCRs), but because it is an unexpected result that differs from most pharmacological theories and clinical intuition, it hasn’t caught on in the last 16 years since the filing of my first patent on September 30, 1992. Although it was previously reported for the opioid and nicotinic receptors, no other research group has characterized and defined their experimental results using predictive biophysical and pharmacodynamic models as we have.

Although at least three companies including Enhanced Pharmaceuticals were formed around such findings, general pharmacological science has been rather slow to follow up on these findings. Truthfully, this puzzles me, because these findings represent a paradigm shift in the pharmacology field toward discovering and making safer and more effective drugs. Big pharma appears to be looking in all the wrong places to extend their patent franchises while ignoring or remaining unaware of technologies such as ours to improve their drugs.

There remains more experimental work to do, but from our studies it appears that these agonist/antagonist drug combinations work well in animals that desensitize differently and that they appear to work after desensitizing a targeted receptor system such as for the Guinea-pig trachea (an accepted experimental system for asthma studies). In our animal studies, there were also less cardiac arrhythmias with our drug combinations than with the agonist (activating) drugs alone. These studies are promising, but need further research. Because our work holds such promise for better asthma, heart failure and Parkinson drugs, we continue to hope that investors will see our potential and rise to the opportunities.

Richard G. Lanzara, M.P.H., Ph.D.
President Enhanced Pharmaceuticals, Inc.

Enhanced Pharmaceuticals

Recently, there was a blog about our company, Enhanced Pharmaceuticals, that elegantly described our technology and the hurdles that it faces for future development.

See - http://avelient.com/BioPharmBlog/2008/07/22/the-agonistantagonist-duel-for-enhanced-pharmaceuticals/#more-113

I couldn’t have said it better.

My wife, who is a doctor, suggests that I need a better way to describe this technology to the public. She has suggested that I use the example of a heroine addict who uses more and more heroine, but achieves less and less of an effect from the drug. Our research suggests that by using a specific combination of heroine and an anti-heroine drug, the effect of the heroine can be maintained and not diminished through continued use.

This research requires additional work, but it holds great promise for designing safer and more effective drugs that target receptors. In our research, we’ve found this to be a general phenomenon for a number of commonly used drugs (usually called G Protein-Coupled Receptor, GPCR, activating drugs, which comprise over 30% of all pharmaceuticals). These drugs include the drugs used to treat asthma, shock, heart failure and Parkinson’s disease among others. So the potential is vast, but alas our funding isn’t.

Anyone wishing to invest in this important venture should contact me at rlanzara@enhancedpharmaceuticals.com for further details.