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.

Experimenting with Tweets

Experimenting with a couple of tweets:

Google Scholar - agonist/antagonist combination - receptor desensitization #Google #science #pharmacology #medicine

A pH dependent electrostatic-mechanism for receptor response? #science #pharmacology #biology #nanotech #biotech

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

A New Exploration Into Science

Since we only know reality through our senses, we should understand how they work in order to understand how our brains work and since our receptors are the molecules that allow our senses to work, we should understand how our receptors work. Surprisingly, the chemical equilibrium of our receptors may function very much like that of a chemical balance poised between two chemical states ( http://www.bio-balance.com/Receptor1.htm ).

This picture is less complex than others have imagined, but it holds promise to understand and simplify many complex and intertwining realms such as where biology, physics and chemistry intersect. How we relate through our senses and bodies to the physical, chemical and biological realms of our world is certainly a worthwhile endeavor to discover. The tools we need to understand these concepts require nothing more than our initial curiosity, patience and some high school algebra.

The physical foundation begins with the study of a simple two pan balance. Although my and most people’s initial reaction is that most everything is already know about the simple balance so what could it possibly have to do with understanding our senses or the world? In fact, if we examine the ways that a balance can be balanced, we find that there are two ways to establish balance. This in and of itself may not seem like much of a breakthrough observation, but by combining and solving for a shift in the mass (weight) from one side to the other we can derive a fundamental equation of equilibrium ( http://tinyurl.com/b8u2vg ) that can be used to understand how our senses function ( http://tinyurl.com/bkf8yb ).

Understanding these concepts is the beginning of understanding how it could be that the receptor process bends the sensory function by a ratio-preserving compression and thereby permits the coupling of the organism to such dynamic ranges of stimuli. By linking these concepts to the chemical concept of Langmuir binding of a chemical entity such as a drug or molecule to another molecule such as a receptor, we can derive mathematical expressions that represent pharmacological dose-response curves ( http://www.bio-balance.com/Graphics.htm ).

Deriving these expressions requires no more than some careful algebra, but leads to several important insights about the physical, chemical and biological relationships that govern how our sensory receptors “see” the world. It turns out that we don’t sense the world in a linear way, which means that we tend to underestimate both the small and larger ends of the stimulus response curve. Perhaps it is in these realms where our senses are not ideal for detecting changes that we may find a better or more accurate understanding of the universe in which we live.

How We Sense Reality - No Really!

The fascinating problem is to truly understand how we “see” reality for who knows, but that our senses may not be entirely up to the task for us to understand the universe. We certainly have found that we need tools that extend our senses into realms where we could before only dream. These tools allowed us to see vast distances both into space and the atomic realms, but perhaps we need a more nuanced approach that understands how we perceive the universe in order to truly understand it.

Since we only know reality through our senses, we should understand how they work in order to understand how our brains work; and therefore, since our receptors are the molecules that allow our senses to work, we should better understand how our receptors work. Surprisingly, the chemical equilibrium of our receptors may function very much like a chemical balance that is poised between two chemical states ( http://www.bio-balance.com/Receptor1.htm ).

This picture is more simple than many others have imagined, but it may hold promise to truly understand and simplify many heretofore complex yet intertwining realms. How we relate through our senses and bodies to the physical, chemical and biological realms of our world is certainly a worthwhile endeavor to discover. The tools we need in order to understand these concepts are nothing more than our initial curiosity, patience and some high school algebra.

The physical foundation begins with the study of a simple two pan balance. Although my and most people’s initial reaction is that most everything is already know about the simple balance so what could it possibly have to do with understanding our senses or the world? In fact, if we examine the ways that a balance can be balanced, we find that there are two ways to reestablish balance. This in and of itself may not seem like much of a breakthrough observation, but by combining and solving for a shift in the mass (weight) from one side to the other we can derive a fundamental equation of equilibrium ( http://tinyurl.com/b8u2vg ) that can be used to understand how our senses function ( http://tinyurl.com/bkf8yb ).

Understanding these concepts is the beginning of understanding how it could be that the receptor process bends the sensory function by a ratio-preserving compression and thereby permits the coupling of the organism to such dynamic ranges of stimuli. By linking these concepts to the chemical concept of Langmuir binding of a chemical entity such as a drug or molecule to another molecule such as a receptor, we can derive mathematical expressions that represent pharmacological dose-response curves ( http://www.bio-balance.com/Graphics.htm ).

Deriving these expressions requires no more than some careful algebra, but leads to several important insights about the physical, chemical and biological relationships that govern how our sensory receptors “see” the world. It turns out that we don’t sense the world in a linear way, which means that we tend to underestimate both the small and larger ends of the stimulus response curve. Perhaps it is in these realms where our senses are not ideal for detecting changes that we may find a better or more accurate understanding of the universe in which we live.

My Discovery

Since filing my first patent on September 30, 1992 (see - http://www.freepatentsonline.com/5597699.html), those who do not understand pharmacological theory want to understand what it is that I’ve discovered. My discovery has been that by combining agonist (or activating) drugs with antagonist (or inhibiting) drugs in specific ratios we can modulate the dose-response relationship to achieve whatever effect we want. This means that we can design new drug combinations that work better than the agonist (or activating) drugs alone. This is a potentially huge market as these drugs comprise roughly more than 30% of all drugs currently being sold. My unique contribution is that by combining drugs, we achieve beneficial effects without having to design new molecular drug entities. These drugs are already on the market and have been FDA approved so their actions and side effects are well known. By using these specific drug combination ratios, we can create safer and more effective drugs now if only we had more interest from the investment community.