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Biochemical Pharmacology Intro

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					       Biochemical Pharmacology
What is it?
1. A fancy way of saying pharmacology
2. A phrase to hide the fact that we are sneaking a subject of
   medical interest into the UW biochemistry curriculum
3. An indication that we are not going to discuss prescriptions
   for your grandmother’s aching knee

What is it not?
1. A claim that we do understand the mechanism of action of
   each practically useful drug in biochemical terms
2. A claim that enzyme mechanisms and receptor structures, or
   even cell biology are sufficient to understand drug action in
   the human body
                 What are ‘drugs’?
Or, more precisely, do they have anything in common at all?
1. The smallest drug:
                What are ‘drugs’?
2. A large drug molecule:
                              What are ‘drugs’?
3. More typical sizes of drug molecules:

                 O                            O
                         S
          H2 N   S                    N
                                      H
                                                   CH3
                                                                   Acetazolamide
                 O   N        N

     H
     C
HC        CH
                                              H2
HC        CH                                  C
                         CH3 O        H2 C          CH2

     C     C
                 H
                 C   N   C    C           N         C     C   OH
                                                                     Enalapril
     H2    H2        H   H                          H
                 C   O   C    CH3                         O
                         H2
                 O

                     H   H
                     C   C                O

            HO                    N
                                  H
                                          C       CH3              Acetaminophen
                     C   C
                     H   H
        Target molecules of drug action (I)
Example: The angiotensin system
                              Angiotensinogen (MW 57000)

N’-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn- 

                                     Renin

   Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu           Angiotensin I

            Converting enzyme

   Asp-Arg-Val-Tyr-Ile-His-Pro-Phe                  Angiotensin II

            Peptidases (degradation)
     Target molecules of drug action (II)
                  Angiotensin II
Receptor                                    vascular smooth muscle cell

                         Phospholipase C        PIP2         DAG
                         (inactive)
G-protein
(inactive)
             G-protein                  Phospholipase C
             (active)                   (active)
                                                               IP3


                          contraction           Ca++ 



                         blood pressure 
     Drug targets in the angiotensin pathway (I)
N’-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn- 

                                            Renin

     Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu                                                Angiotensin I
1.   Renin: Enzyme inhibitors prevent the production of angiotensin I

                                                H                                     H2
                                                C
                                           HC         CH                              C
                                                                               H2 C         CH2
                                           HC         CH
                                                                               H2 C   H     CH2
                                                                                      C
                                   CH3 O        CH2                        O          CH2              OH
                                                                   H                        H               H
                            H3 C      S    C    C          N       C            N     C     C     C    C    C        CH2
Example: Remikiren                         H2   H          H                    H     H           H2   H
                                   CH3 O              O            CH2                      OH                  C
                                                                                                                H2


                                                           N           CH

                                                               C       N
                                                               H       H
     Drug targets in the angiotensin pathway (II)

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu                         Angiotensin I

           Converting enzyme

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe                              Angiotensin II

2.    Converting enzyme: Enzyme inhibitors prevent the production of
      angiotensin II, the active mediator.
                                     H
                                     C
                                HC        CH
                                                                         H2
                                HC        CH                             C
                                                       CH3 O      H2 C        CH2
      Example: Enalapril                       H
                                     C    C    C   N   C    C       N         C     C   OH
                                     H2   H2       H   H                      H
                                               C   O   C    CH3                     O
                                                       H2
                                               O
 Drug targets in the angiotensin pathway (III)
                         Angiotensin II
                                                 vascular smooth muscle cell
     Receptor



                 response (increased blood pressure)                    H
                                                                  N     N

3.    Angiotensin receptor: Receptor blockers                     N     N
      prevent the binding of angiotensin II


                                                         O
                Example: Valsartan                            N
                                                   HO                       CH3

                                                                    O
                                                       H3 C   CH3
      Drugs and physiological mediators (1)

                          Angiotensin II
                                               vascular smooth muscle cell
  Receptor



               response (increased blood pressure)


Asp-Arg-Val-Tyr-Ile-His-Pro-Phe                      Angiotensin II
Sar-Arg-Val-Tyr-Val-His-Pro-Ala                          Saralasin

(Sarcosine = N-methylglycine)
       Drugs and physiological mediators (2)

                             Histamine

                                                     stomach mucosal epithelial cell
   Receptor



               response: HCl secretion                        ulcer

                        C    C    NH2                              C    C    N   C    NH2
                        H2   H2                                    H2   H2   H
Histamine     HN    N                                    HN    N                 NH




 Cimetidine                         H3 C            C     S   C    C    N    C   N    CH3
                                                    H2        H2   H2   H        H
                                           HN   N                            N
                                                                                 C    N
       Drugs and physiological mediators (3)

                                                                  C    C        NH2
                            Histamine              HN        N
                                                                  H2   H2




Allergic     H1 receptor              H2 receptor                               Ulcer
reaction



Cyclizine                                                        Cimetidine

               HC   N   N    CH3   H3 C            C    S   C    C     N    C    N    CH3
                                                   H2       H2   H2    H         H
                                          HN   N                            N
                                                                                C     N
    Drug discovery and development strategies
1. Rational design. Example: HIV protease inhibitors


•   Analyze biological function:
    The protease is essential for
    viral multiplication
•   Obtain crystal structure of
    enzyme, tailor inhibitors to fit
    into active site
•   Test and modify, take to
    clinical testing and
    application
     Drug discovery and development strategies
2. Brute force: Example: ‘Prontosil rubrum’, the first
   sulfonamide antimicrobial agent
                                                             H    H
                                                             C    C       O

                            H2 N               N       N                  S     NH2
                                                             C    C       O
                                                             H    H
•   Systematically test every new        NH2
                                                                          ‘Prontosil rubrum’
    (or old) compound for drug                     H   H
                                                            O
    activity – no matter which                     C   C
                                                                              Sulfanilamide,
                                        H2 N                S     NH2
    purpose it was designed for                                               the active
                                                   C   C    O
                                                   H   H                      metabolite
•   If you stumble upon
    something, figure out how it
                                                                      H   H
    works                                                             C   C           O

                                                           H2 N
                         p-Aminobenzoic acid,
                                                                      C   C           OH
            a precursor of folic acid in bacteria                     H   H
    Drug discovery and development strategies
3. Traditional medicine. Example: Atropine (Atropa belladonna)


                                      OH

•   Isolate the active components     CH2
                                                                   +
    from therapeutically useful       C
                                      H
                                                O             NH2

    and / or toxic plants                   O

•   Elucidate structure, mode of
    action                                                    CH3
                                                               +
                                    H3 C        O   C    C    N        CH3
•   Create novel derivatives with                   H2   H2
                                            O                 CH3
    improved properties

                                           Acetylcholine
    Drug discovery and development strategies
4. Mere chance. Example: Penicillin (Penicillium notatum)


•   Forget to properly cover your
    petri dish
•   Find a mold that kills bacteria
    (Sir Alexander Fleming,
    1928)
•   Wait until somebody purifies
    the active ingredient and
    makes it available for clinical
    use (Florey and Chain, 1942)
               Commercial drug development
In vitro studies   Isolate / synthesize a ‘lead compound’
                   (a candidate drug); vary and optimize

Animal testing     Test efficacy, toxicity, selectivity, ‘pharmacokinetics’

Clinical testing   Test efficacy, toxicity, selectivity, ‘pharmacokinetics’
                   Phase 1: Limited series of healthy volunteers
                   Phase 2: Actual patients with the corresponding disease
                   Phase 3: ‘Double-blind’ studies against placebo or
                   reference treatment

Approval           Review by the authorities – be ready to expend bribes at this
                   stage

Marketing          Patents expire in 15-20 years (varies with country) – after that,
                   generic drugs tend to take out market share

				
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