Various biologically active natural products have played a key role in the identification and characterization of receptors, and such receptors are often named after these compounds (Chapter 12).
Morphine is a classical example of a natural product used for receptor characterization. Radiolabeled morphine was shown to bind with high affinity to receptors in the nervous system, and these receptors were, and still are, named opiate receptors. Some three decades ago, the physiological relevance of these receptors was documented by the findings that endogenous peptides, notably enkephalins and endorphins, served as receptor ligands (agonists). Analogues of morphine have been useful tools for the demonstration of heterogeneity of opiate receptors (Chapter 19) (Figure I.3).
The very toxic and convulsive alkaloid, strychnine, has been extensively studied pharmacologically. Using electrophysiological techniques and tritiated strychnine for binding studies, strychnine was shown to be an antagonist for the neuroreceptor mediating the inhibitory effect of glycine, primarily in the spinal cord. This receptor is currently named the strychnine-sensitive glycine receptor or the glycineA receptor.
Ryanodine a v<x
FIGURE I.3 Chemical structures of morphine, strychnine, ryanodine, nicotine, muscarine, and thapsigargin.
Acetylcholine is a key transmitter in the central and the peripheral nervous system. Acetylcholine operates through multiple receptors, and the original demonstration of receptor heterogeneity was achieved using the naturally occurring compounds, nicotine and muscarine. Whereas the ionotropic class of acetylcholine receptors binds nicotine with high affinity and selectivity, muscarine specifically and potently activates the metabotropic class of these receptors. Using molecular biological techniques, a number of subtypes of both nicotinic and muscarinic acetylcholine receptors have been identified and characterized (Chapters 12 and 16).
The ryanodine receptor is named after the insecticidal naturally occurring compound, ryano-dine. Extensive studies have disclosed that ryanodine interacts with high affinity and in a calcium-dependent manner with its receptor, which functions as a calcium release channel. There are three genetically distinct isoforms of the ryanodine receptor, which play a role in the skeletal muscle disorder, central core disease.
The sesquiterpene lactone, thapsigargin, which is structurally unrelated to ryanodine, also interacts with an intracellular calcium mechanism. Thapsigargin has become the key pharmacological tool for the characterization of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Thapsigargin effectively inhibits this ATPase, causing a rise in the cytosolic calcium level, which eventually leads to cell death. Although the SERCA pump is essential for all cell types, attempts to target thapsigargin toward prostate cancer cells have been made based on a prodrug (see Chapter 9) approach.
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