Summary of structure-activity relationships (SAR

1
Summary of structure-activity relationships
(SARs)
2
What structural elements are necessary for
activity?
3
Removing the oxide bridge (and hydrogenating
double bond, removing one alcohol) produces
levorphanol, which has enhanced analgesic
properties over morphine.
Levorphanol is used to treat severe pain and has
several brand names.
4
Generic Name Levorphanol Brand Names/Synonyms Ant
algin Aromarone Cetarin Dea No. 9220 Dea No.
9733 Dromoran Lemoran Levo-Dromoran Levorfanol
Inn-Spanish Levorfanolo Dcit Levorphan Levorph
anal Levorphanol Dl-Form Levorphanol
Tartrate Levorphanolum Inn-Latin Methorfinan
Czech Methorphinan Orphan Racemethorphanum Racem
ic Dromoran Racemorfano Inn-Spanish Racemorphan
Racemorphan BanInn Racemorphane
Inn-French Racemorphanum Inn-Latinanum
Inn-Latin
5
Surprisingly, its mirror image still has
antitussive properties, but no analgesic
properties
6
Methylating the phenolic hydroxyl group improves
this antitussive activity
7
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

8
(No Transcript)
9
Meperidine

• Pethidine (INN) or meperidine (USAN) (also
  referred to as isonipecaine lidol pethanol
  piridosal Algil? Alodan? Centralgin?
  Demerol? Dispadol? Dolantin? Dolargan? (in
  Poland)1 Dolestine? Dolosal? Dolsin?
  Mefedina?) is a fast-acting opioid analgesic
  drug. In the United States, it is more commonly
  known as meperidine or by its brand name
  Demerol.2Pethidine 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.

10
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.

11
Opioids to treat diarrhea?
12
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?).

13
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,

14
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.

15
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

16
Loperamide (Imodium)

• Loperamide does not cross the blood-brain barrier
  and has no analgesic properties. Tolerance in
  response to long-term 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.

17
Fentanyl
18
Fentanyl

• 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.

19
Fentanyl analogs
20
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.

21
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.

22
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.

23
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.

24
Methadone
25
Methadone

• Methadone/dolophine, was first synthesized in
  1937 by German scientists Max Bockm?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.

26
Methadone

• Methadone was introduced into the United States
  in 1947 by Eli Lilly and Company as an analgesic
  (They gave it the trade name Dolophine?, 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.

27
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.

28
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

29
Schedule II drugs

• Findings required
• The drug or other substance has a high potential
  for abuse.
• 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.
• Abuse of the drug or other substances may lead
  to severe psychological or physical dependence.
• Examples include Morphine, Cocaine,
  Methylphenidate (Ritalin)

30
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.

31
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.

32
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-diarrheals containing
  small amounts of diphenoxylate.

33
Introduction to influenza

• http//microbiology.mtsinai.on.ca/sarswatch/presen
  tations/index.asp
• http//www.pharmasquare.org/flash/Tamiflu.html