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ISBN: 978-0-12-800167-7
ISSN: 0065-7743
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CHAPTER ONE
Content
References 8
#
Annual Reports in Medicinal Chemistry, Volume 49 2014 Elsevier Inc. 3
ISSN 0065-7743 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-800167-7.00001-8
4 John J. Baldwin
For graduate school, I chose the University of Minnesota and was for-
tunate to receive a teaching fellowship. I majored in Organic Chemistry
and minored in Biochemistry, which was structured within the Medical
School. My mentor in synthetic chemistry was Lee Smith, a member of
the National Academy of Science and an expert in quinone chemistry, espe-
cially as it related to vitamin E and coenzyme Q. My minor in Biochemistry
required 2 years of heavy course work. My mentor here was Paul Boyer, the
Nobel Prize winner. Working with both of these men was a great experi-
ence. My research in synthetic organic chemistry and the courses within the
Medical School prepared me well for a future in drug discovery. Work hard;
study harder.
After saying farewell to graduate school in 1960, I joined the Medicinal
Chemistry Department of Merck and Company’s West Point, Pennsylvania,
laboratory. The company, then known as Merck Sharp & Dohme, had
formed through a merger following the discovery at Sharp & Dohme of
hydrochlorothiazide, a game changing medication for the treatment of
hypertension and, in my thinking, the beginning of modern hypothesis-
driven drug discovery.
The Merck laboratory in Rahway, New Jersey, focused on antibiotic
chemistry, which had evolved from the penicillin program; steroids, which
grew out of cortisone synthesis; and vitamins, stemming from their fine
chemicals background. The West Point laboratory was devoted to cardio-
vascular and CNS diseases, antisecretory/antiulcer agents, atherosclerotic
disease, and antiviral agents.
I became involved in many of the West Point programs, including loop
diuretics, xanthine oxidase inhibitors, beta adrenergic blockers, vasodilators,
dopamine agents for Parkinson’s disease, antivirals, and carbonic anhydrase
inhibitors for glaucoma. Learning pharmacology was never ending in the
Merck environment. Work hard; study harder.
The areas that were especially attractive to me were the mechanistic
approach to drug discovery and understanding the biochemistry of disease,
using computationally intensive predictive methods and X-ray crystallogra-
phy of ligand–protein complexes. From this work came Edecrin, Crixivan,
Trusopt, Cosopt, and the antiulcer agent famotidine (Pepcid), which
I identified in the patent literature and championed through the Merck sys-
tem. The work, that led to the first topically available carbonic anhydrase
inhibitor, dorzolamide (Trusopt), has been described in terms of its design,
computational understanding, conformational analysis, and X-ray crystallo-
graphic details of the enzyme/ligand structure.1 This integration of
A Personal Essay: My Experiences in the Pharmaceutical Industry 5
resulting cut-back in employment. Since NCEs are the main factor in raising
valuation, it is unlikely that the merger strategy will increase value to the
pharmaceutical industry. Mergers like Merck/Schering-Plough, Pfizer/
Wyeth, Bayer/Schering, and Sanofi/Aventis will, at best, produce only
short-term stability. History teaches us that such mergers simply do not
increase the productivity on which valuation is based. Such retrenchment
stimulated an outsourcing trend that has accelerated over the past decade.
The layoffs from mergers and outsourcing reached 130,000 between
2005 and 2008, with the total number now well over 300,000 people.4,5
Few companies were spared: the top 10 pharma layoffs in 2011, in rank
order, were Merck, Pfizer, Novartis, Abbott, Astra Zeneca, Teva, Sanofi,
Johnson & Johnson, Eisai, and Bayer.6 WuXi Pharma Tech, one of the first
to recognize the growth in outsourcing and profit from it, went public on
the New York Stock Exchange in 2000 and now has over 6000 employees.
Along with the outsourcing of science, there has been growth in alliance
among large pharmaceutical companies themselves as well as with academic
institutions, all with the idea of sharing both cost and risk.7–9 With the West-
ern markets mature, Big Pharma has turned to the evolving economies as
part of its growth strategy. However, emerging markets have shown resis-
tance to patented medication and a greater interest in improving health
through the availability of low-cost generic drugs.10,11
To overcome the generic competition, Big Pharma has turned to
“branded generics.” Even with cost only somewhat above the local generic
equivalent, pricing remains a problem for Western companies.12 The cost of
patented Western drugs in these economies is being countered by price con-
trols and forced licensing.13 Considering both of these marketing issues, fast-
growing evolving economies may not be the answer for the problems of
today’s pharmaceutical companies.
With the uptick in new FDA approvals in the past 2 years (2011–2012), it
has been suggested that the worst may be over for the productivity decline
we have seen in the pharmaceutical industry.14 However, considering that
programs for these approvals were initiated in the late 1990s to early 2000s, it
is reasonable to predict that the decrease in productivity expected from the
cut-backs will not be felt for at least another 10–12 years.
Things have changed in the pharmaceutical industry since I first walked
the halls of Merck. These changes and the resulting strategies discussed here
have had a negative impact for those who have worked as scientists on drug
R&D and even those who hope to join the exciting adventure of drug dis-
covery. The sky is red, but it is difficult to tell whether it is the sunrise or the
8 John J. Baldwin
sunset. Looking to the future, it is certain that there are many road blocks
along the road to recovery. For synthetic organic chemists, the path ahead
is not bright but should stabilize as the cost advantage of outsourcing to India
and China decreases. In the USA, there will be fewer opportunities for
chemists than there will be for biologically trained scientists as the revolution
in biotechnology continues. Many of these opportunities will be in industry-
sponsored academic laboratories, although the productivity of this indus-
trial/academic strategy may decline over the next decade as Big Pharma
increasingly depends on licensing new products from non-U.S. biotechs.
Government laboratories, such as the National Institutes of Health and
the National Cancer Institute, are unlikely to replace the industrial discovery
machine that gave the world new drugs. Therefore, society will become
increasingly dependent on generic medications as new drugs constitute a
smaller percentage of total sales. With government budget pressures, generic
drugs will become commodities with low profit margins. This may create
the kind of shortages seen recently due to deteriorating production facilities
and poor quality control, which leads to forced closings and recalls by gov-
ernment agencies.
The introduction of biosimilars will be slower than expected, and their
price will not decrease as dramatically as in the case of small-molecule drugs.
The high prices for niche drugs will come under increasing pressure, as dem-
onstrated by the Sloan-Kettering Cancer Center’s experience with the anti-
cancer drug Zaltrap. Similar forced pricing and licensing decisions by India
and other countries on expensive, patented drugs will be a growing problem
for the Western pharmaceutical industry. Companies will begin to rethink
whether it is worth pursuing low-volume drugs where high prices are
needed to recover cost. Similarly, society must decide whether it is willing
to pay high prices for drugs that extend the life of a very ill person for just a
short period of time. These questions pose ethical issues that are difficult
to solve.
For young scientists who received their first chemistry set under the
Christmas tree, all these issues are only challenges for tomorrow. To play
in the sandbox of drug discovery, you must be driven. Work hard;
study harder.
REFERENCES
1. Greer, J.; Erickson, J. W.; Baldwin, J. J.; Varney, M. D. J. Med. Chem. 1994, 37,
1035–1054.
2. Baldwin, J. J. Future Med. Chem. 2011, 3(15), 1873–1876.
A Personal Essay: My Experiences in the Pharmaceutical Industry 9
3. Edwards, J. Leaner Isn’t Meaner for 9 Big Pharma Firms That Tried to Cut Their Way to
Greatness. www.industry.bnet.com/Pharma/10008581/leaner-isnt-meaner-for-9-big-
Pharma.
4. Johnson, L. Merck Plans More Job Cuts. The Reporter, Jul 30, 2011.
5. Novartis Cuts 1,400 US Jobs. The Wall Street Journal, Nov 30, 2011.
6. McBridem, R.; Hallmer, M. http://www.fiercepharma.com/special-reports/top-10-
pharma-layoffs-2011.
7. DeArment, A. http://www.drugstorenews.com/article/astrazeneca-broad-institute-
partner-antibiotic-antiviral-drugs.
8. PharmaLive. http://pharmalive.com/news/Print.cmf?articleid¼877597.
9. Timmerman, L. http://www.xconomy.com/national/2011/06/20/pfizers-idea-to-fix-
the-drug-development.
10. Silverman, E. http://www.pharmalot.com/2012/10/India-pushes-to-end-sale-of-
branded-drugs/.
11. Staton, T. http://www.fiercepharma.com/node/91359/print.
12. Herper, M. http://www.forbes.com/sites/matthewherper/2012/07/12/The-global-
drug-market.
13. Silverman, E. http://www.pharmabt.com/2012/10/australia-plans-to-preview.
14. Christel, M. D. Tide Turns for Innovation. R&D Directions, Jan/Feb 10–11, 2012.
CHAPTER TWO
Adventures in Medicinal
Chemistry: A Career in Drug
Discovery
William J. Greenlee
MedChem Discovery Consulting, LLC, Teaneck, New Jersey, USA
Contents
Acknowledgments 21
References 21
I was born into a family of chemists. My father, uncle, and grandfather were
all chemists. As a result, my brother Mark and I were exposed to laboratories
and the basic concepts of chemistry from an early age. We got used to having
our father enliven family outings by throwing a lump of sodium into the
nearest body of water and having complex chemistry discussions with our
grandfather. I got my own start in the laboratory during high school, syn-
thesizing acetylenes using reactions in liquid ammonia, running Grignard
reactions, and monitoring large-scale distillations for my father’s new catalog
company “Chemical Samples Company.” During that time, my intention
was to study medicine, but I was drawn into the world of organic chemistry
around me. I went on to major in chemistry at Ohio State University, doing
undergraduate research with Paul Gassman. I completed my Ph.D. with
Robert B. Woodward at Harvard University, and after postdoctoral work
with Gilbert Stork at Columbia University, I joined Merck Research Lab-
oratories in Rahway, New Jersey in 1977. It was not a surprise that Mark also
got his Ph.D. in chemistry and has had a long and successful career as a
medicinal chemist.
One thing that drew me to organic and (especially) medicinal chemistry
was the concept of creating a new chemical compound that had never
existed before. The idea that I could do that, and that the compound might
be useful in treating disease was a powerful motivation. Later, when I was
working at the bench, one of my favorite occurrences was spotting the first
#
Annual Reports in Medicinal Chemistry, Volume 49 2014 Elsevier Inc. 11
ISSN 0065-7743 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-800167-7.00002-X
12 William J. Greenlee
By the time I arrived at Merck from Columbia, Art had already started a
program to identify inhibitors of angiotensin-converting enzyme (ACE), to
follow up on earlier discoveries made at Squibb (now Bristol-Myers Squibb).
At the time, the antihypertensive drug Aldomet™ was a successful product for
Merck, but would be off patent in a few years, and a drug that would treat
hypertension with fewer side effects was a major goal. I was asked to join
the effort and was privileged to be part of the team, along with Matt Wyvratt,
Eugene Thorsett, and others, who discovered enalapril and lisinopril, both of
which became important drugs for Merck.3 For many of us, this was our first
experience working with amino acids and small peptides, and doing reactions
and workups in aqueous solution. The ACE inhibitor program was successful
even though the X-ray crystal structure of ACE was not available. Amazingly,
the details of the structure and the fact that ACE has two nonidentical active
sites were not known until many years later.
Adventures in Medicinal Chemistry 13
EtO O HO O
CH3
N N
N N
H O OH H O OH
O O
Enalapril Lisinopril
(Vasotecä) (Prinivilä)
Their elegant work led to a potent and selective hexapeptide inhibitor, but
oral bioavailability was low, and the program was eventually put on hold.
A few years later, we began a new effort in Rahway, now guided by a pub-
lished X-ray structure of human renin. We made significant progress in
reducing the peptide nature of our inhibitors and identifying potent macro-
cyclic inhibitors,4 but we could not achieve the desired profile for an orally
bioavailable inhibitor. At one point, there were over 20 companies with
renin inhibitor programs, but none of the resulting candidates progressed
beyond early clinical trials. It became clear that identifying peptidomimetics
with drug-like properties would be a difficult challenge. It was over 20 years
later (2007) when the first renin inhibitor, aliskiren, was approved for treat-
ment of hypertension.5
It was therefore very exciting when DuPont Pharmaceuticals disclosed
the first potent nonpeptide angiotensin II receptor antagonist and reported
that it had efficacy in a rat model of hypertension. Rather than inhibiting the
formation of angiotensin II, the receptor antagonist losartan blocks the
action of the peptide at its receptor. With encouragement from senior man-
agement, the Merck renin inhibitor program was immediately abandoned,
and all effort shifted to the new target. I soon found myself leading a large
medicinal chemistry effort with an ambitious goal to identify a development
candidate without delay. However, after a few months, Merck announced a
14 William J. Greenlee
Losartan (Cozaarä) 1
H3C O
N H Ph
O N H
O N Ph O
N S N O N O
H N S iPn
H3C N O
Et H3C N O
Et
MK-996 2
nPr
O H3C
N (3-Pyr) N H
O
F H O N O
O O N S nBu
O N O O
N S iPn H3C N
Et Et S
N O
nPr
3 iBu
XR510
Adventures in Medicinal Chemistry 15
One day during our backup program, Pete Siegl, who directed the
Merck pharmacology effort at West Point, called to tell me that one of
our “antagonists” had raised blood pressure when dosed to rats. In fact,
we had discovered the first nonpeptide AT1 agonist, 3.9 This compound
was found to be a full agonist of the AT1 receptor, with a much longer dura-
tion of action than angiotensin II, which is rapidly degraded. Although non-
peptide agonists of peptide G-protein-coupled receptors are now common,
at that time 3 was the only such compound identified outside of the opioid
receptor field. We were astounded by how small a modification in structure
was required to shift an antagonist to an agonist.10 Recently, 3 became the
starting point for design of AT2 selective agonists (without effects on blood
pressure) that are being explored for potential utilities.11
Soon after we completed our angiotensin II program, the discovery of
the vasoactive peptide endothelin was reported, and it was demonstrated
to be the most potent vasoconstricting peptide to date. There was hope that
blocking the endothelin receptors ETA and ETB, or preventing biosynthesis
of endothelin by blocking endothelin-converting enzyme, would provide a
novel (and possibly superior) approach to treating hypertension. Working
from screening leads, we were able to identify potent dual ETA/ETB recep-
tor antagonists, including 4.12 A few of our antagonists also had activity as
angiotensin receptor antagonists, and remarkably we discovered compounds
that blocked all four receptors (ETA, ETB, AT1, AT2) with nanomolar affin-
ity.13 While this work did not continue at Merck, others followed up on
similar leads and were able to demonstrate reduction of blood pressure in
hypertensive patients.14 A number of selective endothelin receptor antago-
nists have been developed by others, but (similar to the situation with the
angiotensin II receptors) the ETA receptor appears to be linked to vasocon-
striction, while the roles of the ETB receptor are still unclear. Interestingly,
both ETA selective (ambrisentan) and dual ETA/ETB antagonists (bosentan,
macitentan) are approved for treatment of pulmonary arterial hypertension.
O OH
O O O
O S
N
H
O
O
4
16 William J. Greenlee
NH2
N N N
N O
N
N
SCH 58261
NH2
N N N
H3C O O N N O
N
N
N
Preladenant
receptor. We were extremely fortunate that one of the hits to emerge from
high-throughput screening became an excellent lead for the program. The
hit was an analog of the natural product Himbacine, which had been syn-
thesized for another program at Schering-Plough. The chemistry team,
headed by Sam Chackalamannil, brought two development candidates for-
ward, but each of these ran into a toxicity issue. Fortunately, the team was
able to address these issues, and the third candidate, SCH 530348
(vorapaxar), moved into clinical trials for prevention of arterial thrombosis.18
I was excited to have the opportunity to co-chair the Early Development
Team for vorapaxar with Madhu Chintala, Head of Pharmacology for the
preclinical program. After completion of the Phase 3 clinical program for
vorapaxar (which enrolled over 41,000 patients), the NDA was filed in
201319 and was approved by the FDA in May of 2014. Vorapaxar (proposed
trade name Zontivity™) is hoped to provide benefits in secondary preven-
tion of heart attack and stroke.20
O H
H H
N O
O H
O
H3C H H
F
Vorapaxar
(Zontivityä)
resources, but were unable to generate leads for our program. Efforts to
work from nonpeptide renin inhibitors in the scientific and patent literature
were also unsuccessful. Reluctantly, we began an effort to design a pep-
tidomimetic BACE-1 inhibitor based on the amyloid precursor protein sub-
strate. Although we were able to identify potent inhibitors with oral
bioavailability using this approach, these inhibitors were P-glycoprotein
(PGP) efflux substrates and showed exceedingly low brain penetration.21
Given these setbacks, it was very exciting when Dan Wyss and Yu-Sen
Wang in our structural chemistry group presented us with fragment hits
that they had identified using HSQC NMR screening. Follow up by
X-ray crystallography provided several confirmed hits, including an iso-
thiourea that bound in the BACE-1 active site, making multiple interactions
with the two active site aspartic acids. The isothiourea was clearly an unde-
sirable group to have in a drug molecule, and a key insight provided by
Zhaoning ( Johnny) Zhu was to replace this basic group with a five-
membered heterocycle (iminohydantoin) in order to make similar interac-
tions. A large team, led by Andy Stamford, worked to optimize the weak
iminohydantoin lead, which later evolved into a six-membered ring series
of iminopyrimidinones.22,23 The BACE-1 program was supported by chem-
ists at Pharmacopeia, and later by chemists at Albany Molecular Research Inc.
As with most CNS programs, achieving potent binding affinity was only part
of the challenge. Although most potent inhibitors in the series reduced beta-
amyloid levels in plasma, reducing them in cerebrospinal fluid (CSF) and
(especially) in cortex was much more difficult. We expected that a balance
of lipophilicity, aqueous solubility, and low PGP efflux would be essential
for good activity in the CNS. However, it also became clear that a high degree
of inhibition of BACE-1 was required for CNS activity. Our failure to
achieve good inhibition of BACE-1 in the cortex became a big concern,
and it was fortunate that we identified an iminopyrimidinone (5) that showed
good activity in both CSF and cortex with an ED50 of 6 mg/kg (po) in rats.24
SCH 900931, later renamed MK-8931, was shown to reduce A-beta-40
levels by over 80% in a Phase 1 rising multiple dose study.25 This inhibitor
is now in Phase 3 clinical studies in Alzheimer’s disease patients. Throughout
the BACE-1 program, the medicinal chemistry team received strong support
from our structural chemistry group led by Corey Strickland, and from other
groups in discovery research. Merck has made a strong commitment to
develop MK-8931 in both mild-to-moderate AD and in patients with mild
cognitive impairment.26 If successful, this inhibitor could make a major con-
tribution to the treatment (and possibly prevention) of this terrible disease.
20 William J. Greenlee
H H
N H3C NH
H CH3
S N HN N
H
S
O
H
O N
Cl
Cl
Fragment lead 5
H N
N H
H N O N
O
Renin inhibitor 6
many changes since I joined Merck over 35 years ago. When I began as a
new medicinal chemist there, I had every expectation that I would be at
Merck my entire career, and in the end I moved only a few miles away
to Schering-Plough, and later had the chance to rejoin Merck after the
merger. No chemist hired today can have the expectation of a long, secure
career with a single company. News of layoffs of medicinal chemists has
become so frequent that it is easy to become cynical about the future of
medicinal chemistry as a career path. In spite of the new uncertainty, there
has never been a more exciting time to be involved in drug discovery, and
I believe that new targets and approaches in discovery research offer a bright
future for medicinal chemists.
What guidance can we offer to medicinal chemists in the industry now or
contemplating a career there? Here are my words of advice: (1) Do your
best, stay focused on drug discovery, and work hard to gain a deep and crit-
ical understanding of medicinal chemistry. Expand your reading beyond
chemistry to acquire a basic knowledge of related disciplines such as phar-
macology, drug metabolism, and toxicology. (2) Build your resume and try
to get one publication, presentation, and patent (at least) from each project
you contribute to, so that your contributions can be recognized. Do not put
off writing the paper, even if you are busy with the next project. (3) Find
ways to contribute more to your projects and to medicinal chemistry.
Become an expert on an important topic and write a review. Look for
opportunities to become involved in medicinal chemistry outside your
company, including volunteering in support of the American Chemical
Society. (4) Above all, maintain a sense of urgency in your work, since what
you are doing is important to the lives of patients. Remember that you have
limited time in your career to make a difference, and take advantage of your
opportunities. I wish you success and happiness in your efforts.
ACKNOWLEDGMENTS
I would like to acknowledge the many outstanding colleagues who have contributed so much
to my career in medicinal chemistry. I have mentioned just a few in the text, without the
intention to overlook others. In addition, I would like to acknowledge Ashit Ganguly,
Michael Czarniecki, Duane Burnett, Deen Tulshian, John Clader, Stuart McCombie,
Cecil Pickett, Ismail Kola, Ann Weber, and Malcolm MacCoss.
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Cordes, E. H. J. Am. Chem. Soc. 1987, 109, 7543.
2. Greenlee, W. J. J. Org. Chem. 1984, 49, 2632.
22 William J. Greenlee
3. Patchett, A. A.; Harris, E.; Tristram, E. W.; Wyvratt, M. J.; Wu, M. T.; Taub, D.;
Peterson, E. R.; Ikeler, T. J.; ten Broeke, J.; Payne, L. G.; Ondeyka, D. L.;
Thorsett, E. D.; Greenlee, W. J.; Lohr, N. S.; Hoffsommer, R. D.; Joshua, H.;
Ruyle, W. V.; Rothrock, J. W.; Aster, S. D.; Maycock, A. L.; Robinson, F. M.;
Hirschmann, R. Nature 1980, 288, 280.
4. Weber, A. E.; Halgren, T. A.; Doyle, J. J.; Lynch, R. J.; Siegl, P. K. S.; Parsons, W. H.;
Greenlee, W. J.; Patchett, A. A. J. Med. Chem. 1991, 34, 2692.
5. Maibaum, J.; Stutz, S.; G€ oschke, R.; Rigollier, P.; Yamaguchi, Y.; Cumin, F.;
Rahuel, J.; Baum, H.-P.; Cohen, N.-C.; Schnell, C. R.; Fuhrer, W.;
Gruetter, M. G.; Schilling, W.; Wood, J. M. J. Med. Chem. 2007, 50, 4832.
6. Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl, P. K. S.; Chang, R. S.;
Lotti, V. J.; Faust, K. A.; Chen, T.-B.; Schorn, T. W.; Sweet, C. S.; Emmert, S. E.;
Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1991, 34, 2919.
7. Chakravarty, P. K.; Naylor, E. M.; Chen, A.; Chang, R. S. L.; Chen, T.-B.; Faust, K. A.;
Lotti, V. J.; Kivlighn, S. D.; Gable, R. A.; Zingaro, G. J.; Schorn, T. W.; Schaffer, L. W.;
Broten, T. P.; Siegl, P. K. S.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1994, 37,
4068.
8. Kivlighn, S. D.; Zingaro, G. J.; Gabel, R. A.; Broten, T. P.; Chang, R. S. L.;
Ondeyka, D. L.; Mantlo, N. B.; Gibson, R. E.; Greenlee, W. J.; Siegl, P. K. Eur. J.
Pharmacol. 1995, 294, 439.
9. Kivlighn, S. D.; Zingaro, G. J.; Rivero, R. A.; Huckle, W. R.; Lotti, V. J.;
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CHAPTER THREE
Contents
1. Introduction 27
2. NAS Modulators of the GABAA Receptor 29
2.1 Endogenous NAS Modulators of the GABAA Receptor 31
2.2 Synthetic NAS Modulators of the GABAA Receptor 32
3. NAS Modulators of the NMDA Receptor 36
4. Conclusions 38
References 39
1. INTRODUCTION
Neuroactive steroids (NASs) are a family of steroid-based compounds
of both natural and synthetic origin, which have been shown to impact cen-
tral nervous system (CNS) function through allosteric modulation of the
GABA(γ-aminobutyric acid)A receptor1–4 and the N-methyl-D-aspartic acid
(NMDA) class of glutamate receptors.5 Respectively, these are two of the
major inhibitory and excitatory neurotransmitter receptor families involved
in synaptic transmission in the brain.
Research over recent years has demonstrated that these receptors can
be either positively (PAM) or negatively (NAM) allosterically modulated
by NAS compounds, an action mediated through binding to allosteric sites.6
Evidence suggests that endogenous NASs (Fig. 3.1), such as all-
opregnanolone (1), are capable of modulating GABAA receptors at concen-
trations that are relevant to their endogenous levels.4,9 Additionally, recent
Figure 3.1 Biosynthesis of endogenous neuroactive steroids (NASs) of the GABAA and
NMDA receptor.7,8
evidence has shown that cholesterol (2) metabolism in the brain is respon-
sible for the generation of a specific, endogenous NAS modulator of NMDA
receptors (24(S)hydroxycholesterol, 3).10
O OH
H H H
H H H H H H
HO HO HO
H
1 2 3
BY
CHAPTER XIII
INTRODUCTION—ANATOMY—REPRODUCTION—BIONOMICS—DISTRIBUTION
—CLASSIFICATION—MICRODRILI AND MEGADRILI
Both at the anterior and at the posterior end the nephridia occasionally
open into the alimentary canal. In various genera the first pair of
nephridia are larger than the others, and open into the buccal cavity; it
seems likely that they serve as salivary glands. A somewhat similar
condition of things exists in Peripatus (vol. v, p. 17). In Octochaetus
multiporus, for example, there is a large tuft of nephridial tubes in the
anterior region of the body, which opens by a long muscular duct into
the buccal cavity. In the same species a good many of the nephridial
tubes open into the posterior section of the intestine, reminding one of
the anal vesicles of the Gephyrea (p. 436) and of the Malpighian tubes
of the Arthropods.