Classes of drug receptors
Drug receptors are mostly proteins. Most of these fall into one of the following categories:
• Ion channels:
– Ligand-gated channels: Ion channels that open upon binding of a mediator
– Voltage-gated channels: Ion channels that are not normally controlled by ligand binding but by changes to the membrane potential
• `Metabolic' receptors – hormone and neurotransmitter receptors that are coupled to biochemical secondary messengers and effector mechanisms. Most metabolic receptors that are drug targets belong to the family of G protein-coupled receptors.
• Cytoskeletal proteins that are involved in cell motility – e.g., actin or tubulin.
Drug target sites that are not proteins include:
• DNA: This is very common with cytotoxic drugs used in cancer therapy, e.g. alkylating agents. These are generally of very poor selectivity and therefore highly toxic. This degree of toxicity is only acceptable in the treatment of life-threatening diseases such as cancer.
• RNA: Although not yet important in clinical practice, antisense oligonucleotides are a very important top-ic in experimental drug development. These are short, synthetic sequences of DNA (or modified versions of DNA), designed to bind to and inactivate RNA tran-scribed from specific genes. While this is a theoretical-ly extremely elegant and versatile approach, it has so far remained largely experimental, despite considerable ef-forts in the last 10-15 years.
• Membranes: Inhalation anaesthetics (diethylether, chlo-roform, and their more modern replacements). The mode of action of these was enshrouded in mystery for a long time, but accumulating evidence now supports di-rect interaction with several ion channels. Nevertheless, there is a remarkably close correlation between the abil-ity of these agents to partition into lipid membranes, as measured by their oil-water partition coefficients, and their narcotic activity; so, in a sense, cell membranes may be considered the targets of these agents.
• Fluid compartments: Osmotically active solutes. These are in fact the only clear exceptions I can think of to the principle that a drug has to bind before acting. Applica-tions include:
– Plasma volume expanders. If blood is lost during trauma, the loss of volume is more immediately threatening than the loss of red blood cells. Replace-ment with salt solutions does not work well because small solutes get rapidly filtrated into the intersti-tial fluid compartment. Only macromolecules are retained in the intravascular space and can prevent filtration of the diluted plasma due to their osmot-ic activity. Commonly used plasma expanders are metabolically inert polysaccharides such as dextran and hydroxyethyl-starch.
– Osmotically acting diuretic agents. These are ap-plied in the treatment of intoxication in order to in-crease the urine volume and accelerate elimination of the poison (`forced diuresis'). The classical ex-ample is mannitol. This sugar is quite similar to glu-cose in structure but does not get metabolized nor re-absorbed from the primary glomerular filtrate in the kidneys.
– Laxatives. Example: Sodium sulfate; effective but obsolete.
However, again, most drugs act directly on receptors that are proteins, and for the rest of this chapter we will deal with this major case only.
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