Summary of structure-activity relationships (SAR’s)
Removal of OH reduces activity
2
HO
3
11
4
Removal increases activity
10
15
12
O
16
9
13
5
14
H
H
HO
N-CH2CH2Ph increases
N-CH2CH=CH2 creates antagonist
1
8
6
N
CH3
7
Introduction of OH increases activity
Oxidation, coupled with reduction of 7,8 C=C, increases activity
Acetylation increases activity
Reduction increases activity
What structural elements are
necessary for activity?
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
N
R1
CH3
R2
N
R3
CH3
7
Quaternary Carbon Center
Basic Nitrogen
Removing the oxide bridge (and hydrogenating
double bond, removing one alcohol) produces
levorphanol, which has enhanced analgesic
properties over morphine.
HO
3
1
10
15
12
11
4
11
13
H
8
6
7
16
9
14
H
10
15
12
16
9
5
HO
3
1
4
O
2
HO
2
N
13
5
CH3
14
H
N
H
8
6
CH3
7
Levorphanol
Levorphanol is used to treat severe pain and has several
brand names.
Generic Name
Levorphanol
Brand Names/Synonyms
Antalgin
Aromarone
Cetarin
Dea No. 9220
Dea No. 9733
Dromoran
Lemoran
Levo-Dromoran
Levorfanol [Inn-Spanish]
Levorfanolo [Dcit]
Levorphan
Levorphanal
Levorphanol Dl-Form
Levorphanol Tartrate
Levorphanolum [Inn-Latin]
Methorfinan [Czech]
Methorphinan
Orphan
Racemethorphanum
Racemic Dromoran
Racemorfano [Inn-Spanish]
Racemorphan
Racemorphan [Ban:Inn]
Racemorphane [Inn-French]
Racemorphanum [Inn-Latin]anum [Inn-Latin]
Surprisingly, its mirror image
still has antitussive properties,
but no analgesic properties
2
1
11
16
10
3
1
11
4
4
15
2
HO
OH
3
12
12
H3C
16
9
9
N
10
15
14
H
13
13
5
5
14
H
N
H
H
8
8
6
6
CH3
7
7
Levorphanol
dextrorphan
analgesic + antitussive
Antitussive only
Mirror
Methylating the phenolic hydroxyl group
improves this antitussive activity
2
11
16
10
OCH3
3
1
4
15
12
9
N
H 3C
14
H
13
5
H
8
6
7
Dextromethorphan (DM)
Antitussive only
Dextromethorphan (DM or DXM) is an antitussive drug that is found in
many over-the-counter cold and cough preparations, usually in the form of
dextromethorphan hydrobromide. It is also commonly taken above the
recommended dosage by users seeking its dissociative effect.
•
•
•
The FDA has approved dextromethorphan for over-the-counter sale as a cough
suppressant. A combination of dextromethorphan and quinidine has been
shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect)
in patients with amyotrophic lateral sclerosis and multiple sclerosis.[3]
Dextromethorphan is being investigated as a possible treatment for pain
associated with fibromyalgia, a chronic rheumatological organic fatigue
disorder.[4]
Dextromethorphan is also useful in breaking addictions to narcotics and other
habit-forming drugs (including nicotine), since it is an inhibitor of many of the
brain receptors involved in narcotic action on the brain. For this purpose, DXM
is more effective when combined with an oxidase inhibitor, which suppresses
its inactivation and increases its half-life; thus it increases the concentration of
DXM in the circulating blood and extends its effective duration.[5]
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
N
R1
CH3
R2
N
R3
CH3
7
Quaternary Carbon Center
O
N
O
CH3
Et
Meperidine
(DemerolTM)
(PethidineTM)
Basic Nitrogen
Meperidine
• Pethidine (INN) or meperidine (USAN) (also referred to
as: isonipecaine; lidol; pethanol; piridosal; Algilｨ; Alodanｨ;
Centralginｨ; Demerolｨ; Dispadolｨ; Dolantinｨ; Dolarganｨ (in
Poland);[1] Dolestineｨ; Dolosalｨ; Dolsinｨ; Mefedinaｨ) is a
fast-acting opioid analgesic drug. In the United States, it is
more commonly known as meperidine or by its brand
name Demerol.[2]Pethidine is indicated for the treatment
of moderate to severe pain, and is delivered as its
hydrochloride salt in tablets, as a syrup, or by
intramuscular or intravenous injection.
Meperidine
• For much of the 20th century, pethidine was the opioid of
choice for many physicians; in 1983 60% of doctors
prescribed it for acute pain and 22% for chronic severe
pain.[3] Compared to morphine, pethidine was supposed to
be safer and carry less risk of addiction, and to be superior
in treating the pain associated with biliary spasm or renal
colic due to its putative antispasmodic effects. In fact,
pethidine is no more effective than morphine at treating
biliary or renal pain, and its low potency, short duration of
action, and unique toxicity (i.e. seizures, delirium, other
neuropsychological effects) relative to other available opioid
analgesics have seen it fall out of favor in recent years, for
all but a very few, very specific indications. Several
countries, including Australia, have put severe limits on its
use or curtailed it outright.[4] Nevertheless, some
physicians continue to use it as a first-line strong opioid.
Opioids to treat diarrhea?
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
16
9
13
5
14
N
H
R1
CH3
H
HO
8
6
R2
N
R3
CH3
7
Quaternary Carbon Center
Basic Nitrogen
Cl
O
N
HO
O
O
Et
N
O
N
CN
N
O
CH3
CH3
CH3
Et
Meperidine
(DemerolTM)
(PethidineTM)
Diphenoxylate
(active ingredient of Lomotil)
(mixture with atropine, to prevent abuse)
Loperamide
(active ingredient of Imodium)
Does not cross BBB, thus no analgesic effect
Diphenoxylate
• Diphenoxylate is an opioid agonist used for the
treatment of diarrhea that acts by slowing
intestinal contractions. It was discovered at
Janssen Pharmaceutica in 1956. It is a congener
to the narcotic Meperidine of which the common
brand name is Demerol. This being the case, this
medication is potentially habit-forming,
particularly in high doses or when long-time
usage is involved. Because of this, diphenoxylate
is manufactured and marketed as a combination
drug with atropine (Lomotilｨ).
Lomotil
• This pharmaceutical strategy is designed to
discourage abuse, because the
anticholinergic effect of atropine will produce
severe weakness and nausea if standard
dosage is exceeded.
• Tablets - round, white, with SEARLE
debossed on one side and 61 on the other
side and containing 2.5 mg of diphenoxylate
hydrochloride and 0.025 mg of atropine
sulfate,
Loperamide (Imodium)
• Loperamide is an opioid receptor
agonist and acts on the μ-opioid
receptors in the myenteric plexus large
intestines; it does not affect the central
nervous system like other opioids.
Loperamide (Imodium)
• It works by decreasing the activity of the
myenteric plexus which decreases the motility of
the circular and longitudinal smooth muscles of
the intestinal wall. This increases the amount of
time substances stay in the intestine, allowing for
more water to be absorbed out of the fecal
matter. Loperamide also decreases colonic mass
movements and suppresses the gastrocolic
reflex.[1]
Loperamide (Imodium)
• Loperamide does not cross the bloodbrain barrier and has no analgesic
properties. Tolerance in response to longterm use has not been reported.However,
loperamide can cause physical
dependence. Symptoms of opiate
withdrawal have been observed in
patients abruptly discontinuing long-term
therapy with loperamide.
Fentanyl
Aromatic Ring
Spacer
2
HO
3
1
11
4
O
10
15
12
9
14
13
5
H
H
HO
16
8
6
N
R1
R2
CH3
N
R3
CH3
7
Quaternary Carbon Center
O
O
N
O
N
CH3
Basic Nitrogen
N
CH2CH2Ph
Et
Et
Meperidine
(DemerolTM)
(PethidineTM)
Fentanyl
(80X more potent than morphine!)
Fentanyl
N
O
N
CH2CH2Ph
Et
• Fentanyl is an opioid analgesic, first
synthesized by Janssen Pharmaceutica
(Belgium) in the late 1950s, with an analgesic
potency of about 80 times that of morphine.
Fentanyl was introduced into medical practice
in the 1960s as an intravenous anesthetic
under the trade name of Sublimaze.
Fentanyl analogs
O
OCH3
N
O
O
N
O
N
CH2CH2Ph
N
Et
N
Alfentanil
(Alfenta)
Fentanyl
(80X more potent than morphine!)
N
Et
Remifentanil
N
OCH3
O
O
N
S
Et
Sufentanil
(Sufenta)
5X more potent than Fentanil
N
OCH3
N
Et
N
O
N
OCH3
N
O
OCH3
N
Et
Carfentanil
(100X more potent than Fentanil!)
O
Fentanyl and analogs
• Fentanyls are extensively used for anesthesia
and analgesia, most often in the operating
room and intensive care unit. Duragesic, by
Janssen Pharmaceutica, is a fentanyl
transdermal patch used in chronic pain
management. Duragesic patches work by
releasing fentanyl into body fats, which then
slowly release the drug into the blood stream
over 72 hours, allowing for long lasting relief
from pain.
Carfentanil
• Carfentanil was discovered by Janssen
Pharmaceutica. It has a quantitative potency
approximately 10,000 times that of morphine and
100 times that of fentanyl, activity in humans
starting at about 1 μg. It is marketed under the
trade name Wildnil as a tranquilizer for large
animals.[1] Carfentanil is intended for animal use
only as its extreme potency makes it
inappropriate for use in humans.
Carfentanil
• It is thought that in the 2002 Moscow theater
hostage crisis, the Russian military made use
of an aerosol form of carfentanil to subdue
Chechen hostage takers.[2] Its short action,
easy reversibility and therapeutic index
(10600 vs. 300 for fentanyl) would make it a
near-perfect agent for this purpose.
Carfentanil
• Wax et al. surmise from the available evidence that
the Moscow emergency services had not been
informed of the use of the agent, and therefore did
not have adequate supplies of naloxone or
naltrexone (opioid antagonists) to prevent
complications in many of the victims. Assuming that
carfentanil was the only active constituent (which
has not been verified by the Russian military), the
primary acute toxic effect to the theatre victims
would have been opioid-induced apnea; in this
case mechanical ventilation and/or treatment with
opioid antagonists would have been life-saving for
many or all victims.
Methadone
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
N
R1
CH3
R2
N
R3
CH3
7
Quaternary Carbon Center
CH3
O
CH3
N
CH3
Methadone
Basic Nitrogen
Methadone
• Methadone/dolophine, was first
synthesized in 1937 by German scientists
Max Bockm殄l and Gustav Ehrhart at IG
Farben (Hoechst-Am-Main, now part of
Frankfurt, Germany) during their search for
an analgesic that would be easier to use
during surgery (and less potentially
addictive, post-op) than morphine.
Methadone
CH3
O
CH3
N
CH3
• Methadone was introduced into the United States
in 1947 by Eli Lilly and Company as an analgesic
(They gave it the trade name Dolophineｨ, which is
now registered to Roxane Laboratories). Since
then, it has been best known for its use in treating
narcotic addiction, although such a use never
became widespread and common until the early
1990's when public policy sought to find ways to
reduce the spread of HIV and AIDS.
‘Scheduling’ of Drugs
• Drugs are classified or “scheduled”
depending on their potential for abuse and
whether or not there is a medical need for a
particular drug.
Schedule I drugs
• Findings required:
• (A) The drug or other substance has a high
potential for abuse.
• (B) The drug or other substance has no
currently accepted medical use in treatment
in the United States.
• (C) There is a lack of accepted safety for use
of the drug or other substance under medical
supervision.
• Examples include Heroin, Cannabis, and LSD
Schedule II drugs
Findings required:
(A) The drug or other substance has a high potential
for abuse.
(B) The drug or other substance has a currently
accepted medical use in treatment in the United
States or a currently accepted medical use with
severe restrictions.
(C) Abuse of the drug or other substances may lead
to severe psychological or physical dependence.
Examples include Morphine, Cocaine,
Methylphenidate (Ritalin)
Schedule III drugs
• Findings required:
• (A) The drug or other substance has a potential for
abuse less than the drugs or other substances in
schedules I and II.
• (B) The drug or other substance has a currently
accepted medical use in treatment in the United
States.
• (C) Abuse of the drug or other substance may lead
to moderate or low physical dependence or high
psychological dependence.
• Examples include anabolic steroids, hydrocodone,
and codeine.
Schedule IV drugs
• Findings required:
• (A) The drug or other substance has a low
potential for abuse relative to the drugs or other
substances in schedule III.
• (B) The drug or other substance has a currently
accepted medical use in treatment in the United
States.
• (C) Abuse of the drug or other substance may lead
to limited physical dependence or psychological
dependence relative to the drugs or other
substances in schedule III.
• Examples include: benzodiazepines and
barbituates.
Schedule V drugs
• Findings required:
• (A) The drug or other substance has a low potential
for abuse relative to the drugs or other substances in
schedule IV.
• (B) The drug or other substance has a currently
accepted medical use in treatment in the United
States.
• (C) Abuse of the drug or other substance may lead to
limited physical dependence or psychological
dependence relative to the drugs or other
substances in schedule IV.
• Examples include cough syrups containing a small
amount of codeine, or anti-diarrheal’s containing
small amounts of diphenoxylate.
Introduction to influenza
• http://microbiology.mtsinai.on.ca/sarswatch/
presentations/index.asp
• http://www.pharmasquare.org/flash/Tami
flu.html