An interesting study on knockout mice [1] suggests that lithium signaling involves
β-arrestin (see Section 5.7); however, the accompanying in
vitro experiments intended to elucidate the intracellular signaling mechanism employed
lithium concentrations much higher than those that can be expected in vivo. ↗
You may have heard of Lipinski’s “rule of five”, which stipulates a
molecular weight of ≤500 Da, places limits on the number of polar atoms, and so
forth, stating all of these constraints using numbers that are multiples of five. These
additional aspects of drug molecular structure will be considered in Chapter 3. ↗
Breakdown of the capillary permeability barrier leads to capillary leak
syndrome, a life-threatening condition with extreme generalized edema. ↗
Indeed, excess gastric acid was considered the cause of gastric
ulcers, since the bacterial pathogen Helicobacter pylori had not
yet been discovered. H. pylori damages the gastric mucous
membrane and initiates ulceration, and antibacterial therapy is now key in the treatment
of ulcers. However, since ulceration is promoted by gastric acid, its reduction remains
important as well. ↗
If you are intrigued by the tetrazole group in the losartan structure, you can find out
more about it in slide 14.2.2. ↗
The Deutschmark was not only fiscally but also artistically superior to the Euro. Maybe
when the Euro finally collapses, we can get it back. ↗
I suppose that something might happen in anaerobic cultures,
with their reducing conditions. I have not looked into the literature on this question,
however. ↗
Stigler’s law of eponymy states that “no scientific discovery
is named after its original discoverer.” Stigler himself names Robert Merton as the
original discoverer of Stigler’s law. ↗
While covalent and irreversible binding coincide with the great majority of drugs, there
are exceptions; see for example slide 15.3.3. ↗
And in case you aren’t, just think of all the money you had no time to spend while
deriving it. ↗
This statement neglects the turnover of the receptor itself by degradation and synthesis,
which we here assume to be slow relative to the reaction and turnover of the drug. ↗
If we define Kintr as the ratio of
active fraction over inactive fraction, then an active fraction of 0.2 in the absence of
ligand corresponds to Kintr = 0.2/0.8 =
0.25. ↗
You may have noticed that each of the three panels in this plot has a different parameter
plotted along the y axis. These will be explained
in Chapter 5. ↗
This is analogous to the oxygen binding kinetics of hemoglobin vs. myoglobin, which is commonly treated at length in introductory
biochemistry classes. ↗
These assumptions follow [9], with the addition of explicit two-state
behavior for the receptor. ↗
The acetylation reaction is straightforward and is carried out with acetyl chloride or
acetic anhydride. Police routinely track shipments of these compounds in order to ferret
out illicit heroin-producing labs. ↗
The transport protein that takes l-DOPA across the blood brain
barrier also transports tryptophan and phenylalanine and is referred to as the l-aromatic amino acid transporter. This same transporter is also
involved in the pathogenesis of phenylketonuria (see slide 10.2.2). ↗
The lobules are separated by thin septa of connective tissue, which are stained bright-red
in this tissue sample. ↗
Amoxicillin is ampicillin with an aromatic hydroxyl group attached. Surprisingly, it has
better oral availability than ampicillin. There may be a rational explanation for this,
but I have not found it. ↗
As noted above, albumin transports fatty acids. Ibuprofen looks a bit like a fatty acid,
and its mode of action involves competing with a fatty acid (arachidonic acid) for binding
to the active site of cyclooxygenase (see Chapter 9). ↗
A somewhat old-fashioned method to accelerate the excretion of such compounds is osmotic diuresis, that is, the application of an osmolyte such as
mannitol that is quantitatively filtrated and retained in the urine, and thus increases
the urine volume due to its osmotic effect. ↗
An even faster way to eliminate phenobarbital is the oral application of copious amounts
of charcoal, also described in [17], which works by “reverse
absorption” into the intestines. ↗
Probenecid was developed to slow down the elimination of penicillin, which is eliminated
in the same way as p-aminohippurate, though not quite at the
same rate. ↗
You may recall that nicotinamide cosubstrates (NAD and NADP) can only accept or donate
electron pairwise, whereas flavin coenzymes (FAD and FMN) can accept or donate them both
singly and in pairs. Flavins therefore can mediate between NAD or NADP and iron-containing
hemes or iron-sulfur clusters that can only accept single electrons. In addition to
cytochrome P450 reductase, we find this arrangement also in nitric oxide synthase and in
the mitochondrial respiratory chain. ↗
The ligand does not seem to be rifampicin itself but a similar compound, although it is
referred to as rifampicin in the pdb file. ↗
Interestingly, the major cytochrome P450 isoform responsible for acetaminophen oxidation
is 2E1, which is induced by ethanol and acetone and also degrades both these inducers.
Also note that, as an alternate route to the pathway shown here, acetaminophen can be
conjugated directly with glucuronic acid or sulfate. ↗
One might think the act of nominating parents for orphans could be described as
“adoption,” but apparently “deorphanization” is more scientific. ↗
On the other hand, individual GPCRs may also couple to more than one G protein;
compare slide 2.5.4. ↗
One might wonder why a protease was not used to activate the receptor. The reason may be
the inherent difficulty in selectively cleaving the receptor without also cleaving and
activating plasma coagulation factors. The use of a peptide receptor agonist avoids this
problem. ↗
In much of the literature on GPCR oligomers, these are assumed to be dimers, but most
studies do not contain experiments that would stringently distinguish between dimers and
larger oligomers. When talking about dimers below, I simply follow the authors of the
cited studies, without examining whether or not they have proven a strictly dimeric
subunit stoichiometry. ↗
The authors of the study cited did not interpret their findings in terms of receptor
oligomerization; however, oligomerization of muscarinic receptors has since been
demonstrated [36]. ↗
Otherwise, heart transplants would be impossible, since the transplanted heart will be
disconnected from those neuronal inputs. ↗
The Nernst equation is really just an application of the Gibbs equation to electrochemical
gradients—all you need to derive it is the Gibbs equation itself and the definition
of the voltage: Δ E = Δ G/zF, with z as the number of charges per ion and F as
Faraday’s constant. ↗
This time is variable; both opening and inactivation are stochastic processes, with
separate rate constants; the rate constant for opening is greater than that for
inactivation. ↗
This reactivation again takes a bit of time; therefore, the membrane will not be excitable
for a short period immediately after repolarization. This time interval is the refractory period. ↗
Note, however, that we do find different channel populations on different cell types, and
this gives rise to action potentials that differ in shape and duration. On nerve and
skeletal muscle cells, action potentials last only a few milliseconds; on heart muscle
cells, half a second, and several seconds on smooth muscle cells. In skeletal muscle, a
contraction is sustained by a repetitive burst of action potentials; in contrast, in the
heart and in smooth muscle, each action potential is sustained for the entire duration of
the contraction. ↗
The lower parts of the excitation-conduction system can also spontaneously produce action
potentials, but do so at a slower rate, and their internal timers get reset each time an
action potential arrives from above. However, when the sinoatrial node fails, another
center—usually the atrioventricular node—kicks in with its own, somewhat
slower rhythm. ↗
Note that this still works out to a flow rate of ~6×106 ions per second.
Unlike glucose transporters etc., which undergo conformational changes with each molecule
transported, ion channels just remain static while the ions zip through in rapid
succession. ↗
The discovery was facilitated by this drug’s liberal recreational use in Vienna in
the late 19th century. Karl Köller, who is credited with the invention,
recounts [43]:
“On a certain occasion, another colleague, Dr. Engel, shared some cocaine with
me, on the tip of his pocket-knife, and observed: ‘It really numbs the
tongue!’ To which I replied: ‘Yes, this has been noticed by everyone who has
eaten it.’ At that moment I realized that I was carrying in my pocket the local
anesthetic I had been searching a few years ago.” ↗
The “ir” stands for “inward rectifier”, meaning that these
channels let K+ ions in more readily than out.
However, the difference between the inward and the outward currents is not very large, and
it is actually the outward permeability that is responsible for their main physiological
function. ↗
Mibefradil was withdrawn from the market due to strong inhibition of cytochrome P450 3A4
[47]. ↗
Such low specificity occurs with channels that transport hydrated ions. The same is also
observed with the nicotinic acetylcholine receptor and some other ligand-gated channels. ↗
The rubidium isotope 86Rb is radioactive and thus is
easily quantified. It is often used instead of K+
because none of the potassium radioisotopes have experimentally convenient half lives. ↗
These mediators are endocannabinoids; we will discuss them in more detail later (see slide
9.7). ↗
As an interesting aside, in neuromuscular synapses, a single presynaptic action potential
is sufficient for triggering a postsynaptic action potential.
This agrees with the fact that a skeletal muscle cell receives input only from a single
nerve cell. ↗
If we assume equal permeabilities for sodium and potassium, we would, according to slides
6.2.2 and 6.2.4,
expect that the EPSP created by the NAR would top out at about −15 mV. This is
still negative, so how can it trigger opening of the adjacent NaV channels? The
answer is that full membrane depolarization is not required for those channels to respond,
since their firing level is at −55 mV. ↗
As you may know, tetanus is caused by tetanus toxin, a protein toxin produced by an
anaerobic soil bacterium, Clostridium tetani. Tetanus occurs
when wounds are infected with this bacterium. The toxin is a protease that cleaves
synaptobrevin, a membrane-associated protein essential for transmitter exocytosis. Tetanus
can be lethal because it interferes with the alternation of muscular contraction and
relaxation required for breathing. Preventive immunization with tetanus toxoid, which is
chemically or genetically inactivated tetanus toxin, protects against the disease. ↗
This might be the last time I’m showing you the structure of cocaine—but no
guarantees. ↗
Aside from reserpine, verapamil and quinidine also inhibit ABC transporters. Intriguingly,
the primary targets of all three drugs are transport proteins other than ABC
transporters. ↗
The decompression of the tiny canal of Schlemm, which drains
surplus fluid from the eyeball, occurs as a side effect of the contraction of the ciliary
muscle that modulates the shape and refractive power of the lens. Muscarinic receptors
induce contraction of this muscle. ↗
Muscle relaxants obviate the need for suppressing pain reflexes in the spinal cord. The
dosage of inhalation narcotics can then be reduced to the lower amount required for
suppressing consciousness in the brain. ↗
An orally applicable ganglion blocker is mecamylamine (slide 3.4.7). ↗
The cells in the anterior pituitary are specialized for the production of individual
hormones; accordingly, since tumors originate from single cells, most hypophyseal tumors
also secrete only individual hormones. On the other hand, damage to the pituitary usually
causes lack of several or all hypophyseal hormones at once. ↗
Birth should proceed within one day after the amniotic sac has burst; if it does not,
oxytocin may be used. My impression from anecdotal evidence is that this is not too
successful and quite often still ends with a Cesarean section—performing the latter
right away seems to me the more sensible option. ↗
From these biochemical effects, it is understandable that patients with excessive thyroid
hormone secretion will experience tachycardia, weight loss, and sweating. ↗
Radioactive iodine isotopes, both 131I− and 129I−, are formed by uranium fission in
nuclear reactors. In case of reactor disasters, people are supposed to swallow large
amounts of non-radioactive iodide in order to saturate their thyroids and prevent
accumulation of radioactive iodine. Thyroid cancer induced by 131I− was the most common form of cancer
observed after the Chernobyl reactor meltdown in 1986. ↗
The roles of iNOS and of cyclooxygenase in inflammation are discussed in chapters 8 and 9, respectively. ↗
It also used to be popular among weight lifters and other competitive athletes, but it no
longer is because it can readily be detected by blood tests. ↗
Interestingly, this even seems to apply to males—see [64]. ↗
The photochemical formation of cholecalciferol proceeds only in the skin. Photons absorbed
by skin pigment are lost to cholecalciferol formation; this likely created the selective
pressure for Homo sapiens to lose most of the skin pigment after
leaving Africa for more Northern climates. Persons with dark skin who live in less sunny
regions should be diligent about vitamin D supplementation. ↗
This appears to be another example of agonist-specific coupling, this time by the vitamin
D receptor; however, I have not been able to find detailed experimental studies on this
point. ↗
Bisphosphonates also have useful antimicrobial activity with some parasites such as Trypanosoma species; this effect seems to be caused by inhibition of
the hexokinase enzymes of these parasites [65]. ↗
Note, however, that peroxynitrite is indeed formed by phagocytes in order to kill ingested
microbes (see section 8.6). ↗
The acidic pH that prevails inside phagosomes will promote protonation of O2•− and ONOO−. This enables them to enter and traverse cell
membranes, which should enhance their microbicidal activity. ↗
Abatement of nitrate tolerance during the weekend was the basis of the Monday headache in
those who worked in Mr. Nobel’s nitroglycerin manufacture. ↗
Arachidonic acid is eicosatetraenoic acid; it is the most important precursor.
Eicosapentaenoic acid, docosahexanoic acid and other ω-3 fatty acids contribute, but
will not be considered here any further. ↗
Inhibitors of thrombocyte aggregation or plasmatic blood coagulation are sometimes
referred to as “blood thinners.” This metaphor is overly simplistic and
misleading. As Einstein remarked, we should strive to make things as simple as possible,
but not simpler. We here have a case of “too simple.” ↗
In a combined immunodeficiency, both cellular immunity, which is
mediated by T-killer cells and other effector lymphocytes, and humoral immunity, that is, formation of antibodies, are compromised.
The drug pentostatin, an inhibitor of adenosine deaminase, is
used to selectively kill lymphocyte-related tumor cells in hairy cell leukemia and other
lymphatic malignancies. ↗
In this context, we should note that an enzyme defect in another nucleotide salvage
enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT), is associated with severe
pathology (Lesch-Nyhan syndrome). ↗
Most solid tumors are treated first with conventional surgery, which removes most of the
malignant cell mass. In contrast, lymphomas and leukemias are treated with cytotoxic drugs
right away; large numbers of malignant cells are thus killed simultaneously, and the
nucleic acids contained within them enter degradation all at once. ↗
Various sugar-binding proteins, or lectins, are found on
macrophages. They serve to recognize polysaccharides on microbial cell surfaces, which
then mediates phagocytosis and destruction of the microbes. ↗
This problem seems to have been overlooked in the recent stampede towards ‘mining
the gut microbiome’ for new antibiotics. Should they indeed exist, such antibiotics
should also be accompanied by resistance genes; and these genes, since they are already
present in humans, would have a particularly easy time of hopping over to some proper
pathogens. ↗
Combination therapy is absolutely essential in the treatment of tuberculosis and leprosy.
The hardy mycobacteria that cause these diseases succumb to antibiotics only slowly, and
their prolonged survival increases their chances of acquiring mutations that confer
resistance. ↗
For an individual carrier plasmid or bacteriophage, the range of host species will often
be quite narrow. However, transposons help resistance genes to move from one carrier
molecule to the next, and thus to cross multiple species barriers successively. ↗
The “toxic” effect of endotoxin results not from any intrinsic biochemical
activity of the LPS molecule but instead from a violent response of the non-specific
immune system to it. ↗
The two types of pumps cooperate synergistically in extruding drugs from the
cell—see [92] and references therein. ↗
The outer membrane in Gram-negatives excludes crystal violet, and therefore prevents the
bacteria from staining dark blue in the Gram stain procedure. In contrast, Gram-positives
absorb and retain the dark-blue dye. The cell wall of mycobacteria excludes both, and
therefore these cells don’t show up in a Gram stain at all. ↗
The thick cell wall enables the mycobacteria to persist inside host phagocytes, which
further impedes access of drugs to bacterial targets. ↗
KatG has both superoxide dismutase and catalase activity, that is, it catalyzes both of
the reactions 2O2−→O2+H2O2
and 2H2O2→H2O+O2. I have not
found a precise equation for the KatG-mediated conversion of INH to the radical
intermediate; the one given in the slide is not to be taken literally. ↗
A crosslinked, stable cell wall is necessary to contain the high osmotic pressure of the
bacterial cytoplasm. If crosslinking is inhibited with vancomycin or β-lactam
antibiotics, the cells will suffer osmotic lysis at physiological extracellular salt
concentrations. Osmotic lysis can be prevented by adding 600 mM sucrose to the
medium. In this way, cell wall-less protoplasts (with
Gram-positive bacteria) or spheroplasts (with Gram-negatives)
can be generated. ↗
Schemes redrawn after reference [97]. The letter R denotes several different substituents that have
been omitted here for simplicity. ↗
Bacterial cells have no ER, and synthesis of membrane or secreted proteins occurs directly
at the cytoplasmic membrane. ↗
Interestingly, overexpression of DNA topoisomerase increases
susceptibility to ciprofloxacin [99]. The cited paper gives a convincing
explanation. ↗
It has recently been shown that daptomycin binds PG and undecaprenol intermediates
simultaneously [102]. Undecaprenol intermediates alone would not
confer selective toxicity (see laspartomycin, above); however, their presence will likely
render bacterial membranes more susceptible to daptomycin, and daptomycin may in this way
also inhibit murein synthesis. ↗
Rendered from coordinates kindly provided by P. Pristovsek. ↗
Coordinates kindly provided by Dr. Maciej Baginski. ↗
The antibiotic used in this experiment is not amphotericin B itself but the related
polyene antibiotic pimaricin. ↗
This ROS toxicity may account for the benefit of glucose-6-phosphate dehydrogenase
deficiency in malaria—lacking regeneration of reduced glutathione prevents
scavenging of ROS, which then inflict damage on the parasites. ↗
The crystallization seems to be initiated by lipids in the parasite’s vacuolar
membranes, but the exact role of the lipids is still a bit contentious [109,110]. ↗
Plot prepared from original data in [111]. β-Hematin structure rendered from
coordinates kindly provided by Katherine de Villiers. ↗
In HIV patients, long-term use of didanosine can give rise to gout (see slide 10.3.6). ↗
Radiation therapy is similar in its mode of action to DNA-modifying cytotoxic drugs.
“Ionizing” radiation creates not only ions but also radicals, which are the
actual cytotoxic agents that react with DNA to induce strand breaks and other kinds of
modifications. ↗
Some of them, of course, don’t stay. From first-hand experience, I would recommend
securing tenure before too many of them are gone. ↗
Chemical name: 2,5-bis-(5-hydroxymethyl-2-thienyl)-furan ↗
The “G” in G1 and G2 denotes “gap”. While
these phases are gap phases with respect to change in cellular DNA content, the cell is
not idle in these stages. The G1 phase, in particular, can be very long and
comprises the time during which a cell performs its specific physiological role. ↗
RXR cooperates also with other nuclear hormone receptors besides RARA, such as thyroid
hormone receptor (slide 7.3.1)
and the pregnane X receptor (slide 4.3). ↗
The translocation is somewhat molecularly heterogeneous, and not all variants or the
resulting protein respond to the treatment equally well. ↗
Sounds complicated? It is actually simplified—see reference [122] for more detail. ↗
The cells that one aims to destroy in immunosuppressive therapy are lymphocytes, which
mediate the autoimmune reactions. The principle is similar as in anticancer treatment, in
that the cells are driven into apoptosis through interference with DNA replication. ↗
Some of the analogues used in antiviral treatment, such as dideoxyadenosine for example,
were indeed originally conceived as anticancer drugs. ↗
Cellular proteins get tagged for degradation by ligation to the small protein ubiquitin.
The protein MDM2 (slide 12.2) is a ubiquitin
ligase that tags p53 for proteosomal degradation. ↗
Melphalan also contains a phenylalanine moiety, which makes it a substrate for amino acid
transporters. Cyclophosphamide undergoes metabolic conversion to another N-mustard
derivative plus acrolein (CH2=CH–CHO), which is an
alkylating agent in its own right. ↗
Fatalities due to chloramphenicol bone marrow toxicity are actually no more frequent than
fatal outcomes of penicillin allergy. Nevertheless, chloramphenicol is shunned, while
penicillin is accepted. I suspect that this is because penicillin allergy kills
instantaneously, and the unfortunate victim will therefore rapidly leave the scene. In
contrast, bone marrow failure due to chloramphenicol is a slow and drawn-out affair that
will cause much dismay and anxiety among a larger number of attendant personnel. ↗
If you are wondering now how this can be done without suppressing the orderly termination
of translation at the regular stop codon, we have no answer for you, but nevertheless
commend you for paying attention. If you were not wondering
about this, you were probably not really studying but just cramming for an exam. ↗
Some viruses, such as rotaviruses, possess a double-stranded genome to begin with.
However, most RNA viruses have single-stranded genomes; one wonders how much RNA
interference may have done to favor the emergence of single-strandedness during
evolution. ↗
The physiological significance of this is that the most common cause of inflammation is
infection, and many plasma proteins, such as antibodies and complement proteins, are
involved in fighting infections. ↗
Leuprolide acetate is a GnRH receptor agonist. However, GnRH receptor stimulation must
occur in a pulsatile fashion in order to trigger release of LH and FSH from the pituitary.
If present continuously, an agonist causes receptor desensitization and decreased LH and
FSH secretion; this is the principle of long term leuprolide acetate application. ↗