Biomedical Engineering Reference
In-Depth Information
HO
HO
N
HO
O
OH
OH
H
O
H
O
N
NH
H
N
CH
3
HO
O
O
O
HO
H
Morphine
Strychnine
Ryanodine
O
O
O
H
O
O
O
H
O
N
O
N
OH
OH
O
O
HO
N
O
Nicotine
Muscarine
Thapsigargin
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 afi nity and selectivity, muscarine specii -
cally 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 identii ed 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 afi nity 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 pharmaco-
logical tool for the characterization of the sarco(endo)plasmic reticulum Ca
2+
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.
I.5.2 N
ATURAL
P
RODUCTS
AS
L
EAD
S
TRUCTURES
Although a number of biologically active natural products have been indispensable as tools for
identii cation and characterization of pharmacological and potential therapeutic targets, these com-
pounds normally do not satisfy the multiple demands on drugs for therapeutic use (Chapter 6).
Thus, although morphine is used therapeutically, it is not an ideal drug, and has to some extent
been replaced by a number of analogues showing slightly lower side effects and higher degrees of
selectivity for subtypes of opiate receptors (Chapter 19). Prominent examples are the
μ
-selective
opiate agonist, fentanyl, and U50,488, which selectively activates the
κ
-subtype of opiate receptors
(Figure I.4).
