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									                                     Analgesia
    Altered behavioral response to pain and diminished
                                                                                  NCH 3
    ability to perceive pain impulses without loss of
    consciousness.
                                                                                   H
    Opioid Analgesic Actions:                                                                         OH
    Analgesia                                                                           O
    Decreased G.I. Motility
    Respiratory Depression                                                     OH
    Euphoria


Classes of Analgesics:             Morpheus - son of Hypnos

Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the periphery as
anti-inflammatories with some CNS activity as well.

Narcotic/Opioids – Analgesic action is in the CNS.        Morphine is the
prototype (From “Morpheus” Greek god of dreams).

Opium is the juice from the poppy and has been used for thousands of
                                                                                                  NCH 3



years to relieve pain.                                                                            H
                                                                                                           OH
                                                                                                      O

                                                                                                OH

                                                                                                      1
                                                            Davis MDCH 5210 - Analgesics (Opioids) 2005
                                            Thomas Sydenham
                                  "Among the remedies which it has pleased
                                  Almighty God
to give to man to relieve his
                                  sufferings, none is
so universal and so efficacious
                                  as opium."
Thomas Sydenham
(1624 - 1689)


                                   He was among the first to describe scarlet fever,
                                   differentiating it from measles and naming it, and to explain
                                   the nature of hysteria and St. Vitus' dance (Sydenham's
                                   chorea). Sydenham introduced laudanum (alcohol tincture of
                                   opium) into medical practice, was one of the first to use iron
                                   in treating iron-deficiency anemia, and helped popularize
                                   quinine in treating malaria.

                                    Derided by his colleagues, Sydenham benefited immensely
17th century engraving of man in    from a consequent detachment from the speculative
Eastern dress collecting juice from theories of his time
the buds of poppy plants



                                                                                                     NCH 3


                                                                                                     H
                                                                                                             OH
                                                                                                         O

                                                                                                   OH

                                                                                                         2
                                                               Davis MDCH 5210 - Analgesics (Opioids) 2005
                  War On Drugs.




Early victims of the War On Drugs. A battle-scene                         NCH 3


from the First Chinese Opium War (1839-42)                                H
                                                                                  OH
                                                                              O

                                                                        OH

                                                                              3
                                    Davis MDCH 5210 - Analgesics (Opioids) 2005
               Endogenous Opioids Endorphins and Enkephalins

Small peptides. -endorphin is a 31 amino acid peptide.
Examples:

Tyr – Gly –Gly – Phe – Met   ( Met Enkephalin)

Tyr – Gly –Gly – Phe – Leu   ( Leu Enkephalin)




                                                                                                NCH 3


                                                                                                H
                                                                                                        OH
                                                                                                    O

                                                                                              OH

                                                                                                    4
                                                          Davis MDCH 5210 - Analgesics (Opioids) 2005
  Enkephalin Properties:

•Similar activity to the opioids (analgesia)
•Similar addiction and withdrawal effects
•Enkephalins are antagonized by opioid antagonists (same receptor)
•Enkephalins are rapidly inactivated by specific peptidases in the brain.

Details of Enkephalin Mechanism

•Enkephalinergic system exists to modulate pain.

•Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and
causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits nerve
cell activity. Opioids also bind the enkephalin post-synaptic receptors.

•Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin or
exogenous opioids.

•Opioid binding to the “auto-receptor decreases enkephalin release, this results
in tolerance,
                                                                                                     NCH 3


                                                                                                     H
                                                                                                             OH
                                                                                                         O

                                                                                                   OH

                                                                                                         5
                                                               Davis MDCH 5210 - Analgesics (Opioids) 2005
Enkephalinergic Neurons




                                                          NCH 3


                                                          H
                                                                  OH
                                                              O

                                                        OH

                                                              6
                    Davis MDCH 5210 - Analgesics (Opioids) 2005
          Second Messenger Effects - Enkephalin SAR
Second Messenger Effects
Opioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The
physiological response is to make more enzyme to compensate.

Tolerance develops. When opioids are removed, an excess of AC is available and now
active, overstimulation produces withdrawal.

Opioid antagonists don’t cause withdrawal symptoms in naive subjects.

Enkephalin SAR

L-tyrosine is required along with a terminal NH2.
D-tyrosine is inactive
Phe is very important, partial or full loss of activity occurs upon substitution
D-amino acids at other positions, particularly the Gly’s decrease hydrolysis and therefore
increase potency.
D-amino acids and bulky amino acids affect activity and may increase receptor selectivity
Rigid analogs are useful for assessing preferred conformations and may be more selective
for different receptors.                                                               NCH             3


                                                                                                   H
                                                                                                           OH
                                                                                                       O

                                                                                                 OH

                                                                                                       7
                                                             Davis MDCH 5210 - Analgesics (Opioids) 2005
                           Analgesic Receptors 


All bind morphine and endogenous enkephalins, all are antagonized by
naloxone

 is the analgesic receptor. 2 subtype is associated with respiratory
depression and with GI receptors.

 may be the antitussive receptor for codeine and related compounds. The
antitussive actions of  and  specific agonists are antagonized by naloxone.
However dextromethorphan sites don’t bind codeine, and binding at these
sites (likely  sites) are not antagonized by naloxone. Therefore, there are
at least two antitussive receptors.



           J. Pharm. And Exp. Therapeutics (2000) 292, 803-809

  is also analgesic. Binding site of several mixed agonist/antagonist
 compounds.
 Pentazocine – agonist at , antagonist at                                                          NCH 3

 Buprenorphine – partial agonist at  (slowly dissociates), antagonist at                          H

 Butorphanol – agonist at , antagonist at                                                              O
                                                                                                             OH


                                                                                                   OH

                                                                                                         8
                                                               Davis MDCH 5210 - Analgesics (Opioids) 2005
                             Receptors - continued
 agonists produce psychotomimetic/dysphoric side effects
similar to those seen with the  receptor agonist PCP. High
doses of pentazocine have this effect.

 and  receptors are not analgesic on their own, but specific 
agonists do cause analgesia.

          Nature (1996) 383, p.759; pp.819-823.

 knockout does not produce analgesia with morphine, Perhaps
 receptors interact.  binding could induce activity in 
receptors.

Other points:
 (MOR) knockouts are fully functional, no adverse side effects.

Conclusion: opioid system is not active under normal resting
conditions. That’s why you don’t get addicted to your own
enkephalins.
                                                                                                    NCH 3


                                                                                                    H
                                                                                                            OH
                                                                                                        O

                                                                                                  OH

                                                                                                        9
                                                              Davis MDCH 5210 - Analgesics (Opioids) 2005
Opioid receptors and trans-membrane helices




                                                                      NCH 3


                                                                      H
                                                                               OH
                                                                          O

                                                                    OH

                                                                          10
                                Davis MDCH 5210 - Analgesics (Opioids) 2005
    Delta Opioid Receptor Simulation




Figure 3. The starting
configuration for the simulation
of the hDOR in a lipid bilayer




                                                                                                         NCH 3


                                                                                                         H
                                                                                                                  OH
                                                                                                             O
                                   Mahalaxmi Aburi et al. Protein Sci 2004; 13: 1997-2008
                                                                                                       OH

                                                                                                             11
                                                                   Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                    Receptor Communication


   Opioids have excitatory effects in multiple regions of the nervous system.
   Excitation by opioids is generally attributed to inhibition of inhibitory
   pathways (disinhibition). However, recent studies indicate that opioids can
   directly excite individual cells. These effects may occur when opioid
   receptors interact with other G protein coupled receptors, when different
   subtypes of opioid receptors interact, or when opioids transactivate other
   receptors such as receptor tyrosine kinases. Changes in the relative level
   of expression of different receptors in an individual cell may therefore
   determine its functional response to a given ligand. This phenomenon could
   represent an adaptive mechanism involved in tolerance, dependence and
   subsequent withdrawal.
                                                                                                          NCH 3


                                                                                                          H
                                                                                                                   OH
                                                                                                              O

From inhibition to excitation: Functional effects of interaction between opioid receptors               OH

Life Sciences Volume 76,, (2004), Pages 479-485                                                               12
                                                                    Davis MDCH 5210 - Analgesics (Opioids) 2005
    Loss of morphine-induced analgesia, reward effect and withdrawal
    symptoms in mice lacking the mu-opioid-receptor gene.

   Nature. (1996) 383:819-23.


ABSTRACT: Despite tremendous efforts in the search for safe, efficacious
and non-addictive opioids for pain treatment, morphine remains the most
valuable painkiller in contemporary medicine. Opioids exert their
pharmacological actions through three opioid-receptor classes, mu, delta and
kappa, whose genes have been cloned. Genetic approaches are now available
to delineate the contribution of each receptor in opioid function in vivo.
Here we disrupt the mu-opioid-receptor gene in mice by homologous
recombination and find that there are no overt behavioural abnormalities or
major compensatory changes within the opioid system in these animals.
Investigation of the behavioural effects of morphine reveals that a lack of
mu receptors abolishes the analgesic effect of morphine, as well as place-
preference activity and physical dependence. We observed no behavioural
responses related to delta- or kappa-receptor activation with morphine,
although these receptors are present and bind opioid ligands. We conclude
that the mu-opioid-receptor gene product is the molecular target of
morphine in vivo and that it is a mandatory component of the opioid system                        NCH 3

for morphine action.                                                                              H
                                                                                                           OH
                                                                                                      O

                                                                                                OH

                                                                                                      13
                                                            Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                                                                      SAR - 1
                                NCH 3(R2 )                               NCH 3
                                      8
                                  14       7
                                H          6                             H
                      1                        OH(R1)                                 OH
                                          5
                      2               O                                      O
                          3
                              OH(R)                                    OH

                    SAR-SAR-SAR-SAR-SAR-SAR

           1.  Modifications at the phenolic OH (3-position).
     2.    Decrease analgesic potency, increase antitussive activity.



     Numbering of morphine is based on phenanthrene.
     The important positions, 3,6,7,8,14 are indicated.

  1/7 as active compared to morphine for pain. Not a better antitussive.
  Codeine only binds 1/3000 the affinity of morphine to  receptor. Analgesic
  action is due to morphine.

R = -OCH3                     R1 = -OH                  3-O-methy lmorphin e (Codeine)
                                                                                                                         NCH 3


                                                                                                                         H
            O                                                                                                                     OH

R=        O CCH 3             R1 = -OH                  3-O-acetylmorph ine, 1 x                                             O

                                                        morph ine                                                      OH

                                                                                                                             14
                                                                                   Davis MDCH 5210 - Analgesics (Opioids) 2005
SAR - 2           NCH 3                         NCH 3
                                                                                         (NR) H3 CN
                                                                                                         14
                                                                                                              8
                                                                                                                      7
                                                                                                     H
                                                                                             1                    6   OH (R1)
                  H                             H                                           2             O
                           OH                                OH                                  3
                                                                                                 OH (R)
                       O                            O

                OCH3                        O       CH3

                                                O

  2. Modifications at the alcoholic OH ( 6 position). Substituents increase
  potency by increasing liposolubility. Increased potency and addiction.


     R=    OH               R=      OCH3                heterocodeine (5 x morphin e)
                                                        Poor antitu ssive
                                        O
     R=    OH               R=      O CCH 3             6-acetylmorphin e. 4-5 x
                                                        morph ine.
     R=    OH               R1 = carbonyl               morph inone - 1/3 x morphin e

                                                                                                                          NCH 3


                                                                                                                          H
                                                                                                                                   OH
                                                                                                                              O

                                                                                                                  OH

                                                                                                                              15
                                                                       Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                                                                 (NR) H3 CN
                                                                                                                     8
                3. Modifications of both 3 and 6 positions (hydroxyls).
                                                                                                                14           7
                                                                                                            H
                                                                                                    1                    6   OH (R1)
                  O                            O                                                    2            O
   R=       O CCH 3             R=        O CCH 3       3,6-O-diacetylmorphin e, 2 x                    3
                                                                                                        OH (R)
                                                        morph ine. (Heroin)



  Greater euphoria, higher addiction liability. Probably metabolized to 6-O-acetate
  then morphine in CNS.
                                                             HEROIN 

                                                    A powerful remedy for coughs

      NCH 3                           NCH 3


        H                             H
                      O                             O       CH3
            O                              O
                                                        O
    OH                            O        CH3
                                                                                                                         NCH 3
                                      O
                                                                                                                         H
                                                                                                                                     OH
                                                                                                                                 O




SAR - 3
                                                                                                                     OH

                                                                                                                             16
                                                                            Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                                                                  (NR) H3 CN
4A. Reduction of the 7,8 double bond. Compounds with same
                                                                                                                      8
                                                                                                                 14           7

Substituents at R and R1 and a reduced double bond have the same                                     1
                                                                                                             H
                                                                                                                          6   OH (R1)
potency as morphine. “dihydromorphine”, “dihydrocodeine.”                                            2            O
                                                                                                         3
                                                                                                         OH (R)
4B. Reduction of the 7,8-double bond and oxidation of 6-OH to carbonyl.



                                                              Hydromo rphone , 7 x morphin e
       R=    OH                      R1 = carbonyl            (Dilaudid ). Less sedation, less
                                                              nausea.

      R = -OCH3                      R1 = carbonyl            Dihydro codeinon e,
                                                              Hydro codone, 4 x codeine as an
                                                              antitu ssive. (Dicodid)




                  NCH3H H                       NCH3H H                    NCH3H H
                            H                             H                               H
                                H                             H                               H
                  H                             H                           H
                                OH                            O                               O
                                                                                                                                  NCH 3
                      O                              O                            O
                                                                                                                                  H
                                                                                                                                           OH
             OH                              OH                          OCH3                                                         O

                                                                                                                              OH


SAR - 4                                                                         Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                                                                                                      17
                                                                                               (NR) H3 CN
 5. Hydroxylation of C-14, reduction of 7,8-double bond, oxidation                                             14
                                                                                                                    8
                                                                                                                            7

 of 6-OH. Generally increases potency.                                                             1
                                                                                                           H
                                                                                                                        6   OH (R1)
                                                                                                  2             O
                                                                                                       3
 R=       OH                R1 = carbonyl           Oxymorphon e (Numorphan). 10                       OH (R)
                                                    x morphin e
 R = -OCH3                  R1 = carbonyl           Oxycodone (Percodan) 1 x
                                                    morph ine as analgesic.


                       NCH3H H                NCH3H H
                                  H                      H
                                      H                      H
                      HO                     HO
                                      O                      O
                            O                       O

                     OH                      OCH3

6. Modifications at Nitrogen. 2o N << 3o; 4o Nitrogen is inactive. -N(R) groups larger
than CH3 produce antagonists.

      N(R) = N CH2 CH CH2       “N-allyl ”              N-allyl morphin e (Nalorphin e) is
                                                        a mix ed agonist/antagoni st.
                                                        “weak or partial agoni st”                                              NCH 3


                                                                                                                                H
                                                                                                                                         OH

 Nalorphine will compete with more potent agonists to cause withdrawal.
                                                                                                                                    O




SAR - 5
                                                                                                                        OH

                                                                                                                                    18
                                                                             Davis MDCH 5210 - Analgesics (Opioids) 2005
  7. Substitute at Nitrogen plus reduce 7,8-double bond,                                           (NR) H3 CN
                                                                                                                   14
                                                                                                                        8

  hydroxylate C-14, oxidize C6-OH to the carbonyl.
                                                                                                                                7
                                                                                                               H
                                                                                                       1                    6   OH (R1)
                                                                                                      2             O
                                                                                                           3
                                                                                                           OH (R)
 N(R) = N CH 2 CH CH 2         R1 = carbonyl          Naloxone (Narcan). 7 x better
                                                      antagonist than nalorph ine.

                               R1 = carbonyl          Naltrexone (Traxan) better oral
 N(R) = N CH 2
                                                      activity than n aloxone .


                                                CH2 CH CH2
                 CH2 CH CH2
            N
                                            N                              N
                                                 OH    H                          OH         H
                                                        H                                     H
            H
                          OH                           O                                     O
                   O                             O                               O
         OH                              OH                              OH

                 Etorphine (an oripavine)                        NCH 3   H 3C   CH 2 CH 2 CH 3
                                                                         H
                 200 x Morphine,                                                OH                                                  NCH 3

                 Approx. 8000 x Morphine                                                                                            H
                                                                            OCH 3
                 in animals.                                        O
                                                                                                                                             OH
                                                                                                                                        O

                                                                                                                            OH


SAR - 6          Puts elephants to sleep.                     OH

                                                                                 Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                                                                                                        19
We need analgesics with less respiratory depression that are also less addictive.

Morphinans.
                            NCH 3                        NCH 3


                            H                            H
                                      H                             H


                        OH                            OCH 3
     levorphanol (Levo-Dromoran)              (+) or (d) dextromethorphan

     (-) isomer is an active analgesic, 5 x   Antitussive activity similar to
     morphine                                 codeine, no analgesic activity, no
     (+) isomer is an active antitussive      addiction liability.
     (dextrorphanol) and a poor analgesic

                        N       OH            butorphanol (Stadol)

                                              4 x morphine as agonist
                                                                                                              NCH 3
                                              1 x morphine as antagonist
                                       H      -low(er) addiction liability                                    H
                                                                                                                       OH

                                              “better for acute pain”                                             O

                                                                                                            OH



SAR - 7              OH
                                                                                                                  20
                                                                        Davis MDCH 5210 - Analgesics (Opioids) 2005
   Benzomorphans.

   Pentazocine (Talwin)
                                                              N
   Mixed agonist/antagonist. Used as
   an agoni st for pain. 1/3 x morphine.                     H3C
   Low addiction.                                                       CH 3


                                                             OH


 4-phenyl piperidines. Completely synthetic


                                     CH 3                           NCH 3
                                 N
          O    OCH 2 CH 3
                                                                    H
                   NCH 3                                                           OH
                                                OCH 2 CH 3
                                                                          O
                                            O                                                                  NCH 3
                                                                   OH
                                                                                                               H
                                                                                                                        OH
     Meperidine
                              Meperidine                      Morphine
                                                                                                                   O




SAR - 8
                                                                                                             OH

                                                                                                                   21
                                                                         Davis MDCH 5210 - Analgesics (Opioids) 2005
 4-phenyl piperidine SAR.
 •Phenyl and piperidine rings are required.
 •3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases
 potency (fentanyl).
 •You can’t make an antagonist by substituting the nitrogen.
 •Addition of a meta hydroxyl to the aromatic ring increases potency and addiction
 (analogous to morphine)
 •C-4 is usually quaternary. Alkyl esters are common for this class. Placing a nitrogen
 between the rings increases potency (fentanyl again)



 Properties of Phenylpiperidines.

 Bemidone – 3 x Meperidine
 -Prodine (Nisentil) – 2 x Meperidine. Not used anymore
 Fentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration. Used as
 an analgesic and also as an anesthetic either with or without droperidol. (About
 500 x Meperidine analgesic potency).
 Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can be
 dispensed with Atropine
 Loperamide (Imodium) – Polar groups decrease intestinal absorption and eliminate                   NCH 3


 CNS activity. Inhibits GI muscle contraction by interaction with opioid receptor.                  H
                                                                                                             OH
                                                                                                        O

                                                                                                  OH

                                                                                                        22
SAR - 9                                                       Davis MDCH 5210 - Analgesics (Opioids) 2005
                        O       OCH2 CH3

                                      NCH3                                   OCH2 CH3
                                                                    O
            HO                                                                                CN
                       Bemidone                                                 N

                    O         OCH2 CH3
                                                                   Diphenoxylate
                                     NCH3

                       H3 C

                       -prodine                                        HO                        O

                    O                                  Cl                        N
                              CH2 CH3                                                             N(CH3 )2

                    N
                                 N                                 Loperamide

                   Fentanyl
                                                F

                        N
                                        O

                                                                                                         NCH 3

                   N                                                                                     H
                            O                                                                                     OH
                                                                                                             O
                   N
                                                                                                       OH


SAR - 10   Droperiodol (a butyrophenone, not a phenylpiperidine)                                             23
                                                                   Davis MDCH 5210 - Analgesics (Opioids) 2005
 3,3- Diphenylpropyl amines.

 Methadone
 1x morphine
 less sedative
 longer acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent
 heroin withdrawal

 Propoxyphene
 d isomer (Darvon) – analgesic with 1/2 the potency of codeine
 l isomer (Novrad) – antitussive action only.




                                                                CH 3
                               CH 3                                                    CH 3
                                          CH 3
                                                     CH 2   C   CH      CH 2       N
                     C    CH 2 CH     N
                                                            O                          CH 3
                                          CH 3
                 O       CH 2CH 3                     O     CH 2 CH 3
                                                                                                                     NCH 3


                                                                                                                     H
               Methadone                         Propoxyphene (d or l isomer)                                                 OH
                                                                                                                         O

                                                                                                                   OH


SAR - 11                                                                                                                 24
                                                                               Davis MDCH 5210 - Analgesics (Opioids) 2005
                                            Fentanyls
                                                          O
                                                  O
                    O           N                                                           O     O
                                                                                        O
                                                      N
                        N                                              N
                                                                                   O        N
                                                                                                      N
                                                                               N   N                           O
                                                                                N N
                                                                                                           O

                                                          Alfentanil                        Remifentanil
                    Fentanyl




                            O                                      O       O
                   O                                      O

                        N                                      N
                                 N                                             N

                                     S



                        Sufentanil                            Carfentanil



Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 g/h) Therapeutic
index=400, morphine = 70
Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration                                                             NCH 3

Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000
Sufentanil - 5-10x Fentanyl, used for heart surgery.
                                                                                                                             H
                                                                                                                                      OH
Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue                               O

Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.                 OH

                                                                                                                                 25
                                                                                       Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                 NCH 3


                                                 H
                                                          OH
                                                     O



SAR - 12                                       OH

                                                     26
           Davis MDCH 5210 - Analgesics (Opioids) 2005
                                                 NCH 3


                                                 H
                                                          OH
                                                     O



SAR - 13                                       OH

                                                     27
           Davis MDCH 5210 - Analgesics (Opioids) 2005

								
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