CHAPTER 1
Extracellular and Intracellular Signaling – a New Approach to Diseases and Treatments
JAMES DAVID ADAMS, JR.,*a ERIC J. LIENa AND KEITH PARKERb
a Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue,
Los Angeles, CA, USA 90089; b Department of Pharmaceutical Sciences (MPH102) BMED, School of Pharmacy and Allied Health Sciences, Skaggs Building, Missoula, MT, USA 59812-1552
1.1 Introduction
1.1.1Linear Model of Drug Receptor Interactions
The body and mind depend on a variety of receptors and endogenous, extracellular ligands in order to maintain health. In the past, a simplistic, linear model of ligand receptor binding has been used with great success for drug development.
Ligand þ Receptor ! Ligand-Receptor complex ! Effect |
ð1:1Þ |
This model has led to a simplistic, linear model of disease where one aberrant gene produces one abnormal protein leading to the induction of one disease. It is now clear that the body does not function according to these linear models.
RSC Drug Discovery Series No. 10 Extracellular and Intracellular Signaling
Edited by James D. Adams, Jr. and Keith K. Parker r Royal Society of Chemistry 2011
Published by the Royal Society of Chemistry, www.rsc.org
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Chapter 1 |
Instead, the body makes use of a complex interacting system of intracellular matrices, called signal transduction networks, in order to maintain health. Proper health depends on maintaining the proper balance of these intracellular signal transduction networks. Most of us are born healthy and could stay healthy, if we knew how. Many economically important diseases are not caused by single gene aberrations, but are caused by lifestyle changes that alter many genes and the balance of signal transduction networks.
1.1.2Matrix Model of Drug Receptor Interactions
fCalcium mechanismsg
fPhospholipasesg Ligand-Receptor complex fProtein kinasesg ! Effect
fNAD mechanismsg |
(1.2) |
The model above is intended to show that matrix division and matrix multiplication lead to drug e ects. For instance, phospholipase mechanisms liberate active lipids that may multiply the e ects of a drug receptor interaction. This is synergism. However, protein kinase mechanisms that phosphorylate proteins, may decrease, or divide, the e ects of a drug receptor interaction. This is dysynergism. For each ligand receptor interaction there may be synergism and dysynergism by many signal transduction networks (only four are shown) that are involved in processing the interaction and producing the e ect. Equation (1.2) is simplified since many receptors can exist in active and inactive states, or states of altered activity. Ligand binding may have di erent e ects depending on the state of the receptor at binding.
There are many endogenous, extracelllular ligands, made in the body, that produce e ects upon receptor binding. These extracellular ligands, such as the adipokines and the cytokines, modify the balance of normal intracellular signal transduction networks in order to maintain health or cause disease. Drugs tend to mimic these endogenous ligands, in terms of chemical structure and receptor interactions. It is likely that only a minority of the endogenous ligands are currently known. Many more will be discovered in the future. Endogenous ligands include lipoxins, prostaglandins, endocannabinoids, enkephalins, endorphins, adipokines, cytokines, hormones, neurotransmitters and many others. Many of these endogenous ligands are produced locally, act locally and have short half-lives. This makes them superior to drugs that must penetrate to the site of action and persist until the e ect is attained. Drugs are usually designed to have half-lives of about 24 hours so that patients can take them daily, or on a convenient schedule. The long residence time of drugs in the body increases the risk of toxicity.
In general, for each receptor in the body there is at least one endogenous agonist and one antagonist. Therefore, health depends on the balance of