Drugs
1 Drugs
Lecture Outline
- Definitions
- How Drugs Function
- Case Study: Aspirin
- Biochemical ``problem''
- Traditional solution
- COX-2 inhibitors
- Morphine, Codeine, & Heroin
- Structural Relationships
- Insights into Drug Design
2 OldWives' Tales
Numerous 'Home remedies' have been known for a long time.
- Chicken Soup - Actually appears to work !?
- Fish is brain food - Good source of protein and beneficial fats.
- Carrots help vision - Good source of Vitamin A.
- Willow bark tea to relieve pain (Hippocrates, 4 B.C.) - Natural source of 'aspirin'.
- Don't swim right after eating - Well, they can't all be right.
3 Definition of a Drug
- Textbook (p. 378)
``Drugs ... are substances that prevent, moderate, or cure illnesses.''
- A more general definition
A drug is any external substance that alters biochemical reactions in the body when taken - it changes some body function(s).
4 The Ideal Drug
The perfect drug doesn't exist. However, there are certain characteristics that are desired in almost any drug.
- Achieves desired effect
- Extent of change varies by dosage
- Time of effect controllable
- No undesirable side effects
- Inexpensive
5 Sample Drug Structures
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| Aspirin | Ibuprofen |
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| Caffeine | Codeine |
Note that these are relatively simple molecules.
6 Hormones
- Hormones are ``simple'' chemical released into bloodstream.
- All cells have a chance to ``see'' hormone
- Only appropriate cells have receptors for any particular hormone.
An imperfect analogy.
Lots of different cars (different hormones) drive on the streets in your neighborhood (bloodstream), but only your family's cars have the garage-door-opener (specific hormone) that opens your garage door (specific type of cell).
7 Lock-and-Key Model
Receptors located on the surface of cells only bind a very limited number of substrates (often only one). The receptor is typically much more complicated (larger) than the substrate (hormone) that binds to it. (For an analogy, note that a lock is much more complicated than a key).
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8 Case Study - Aspirin
- Our bodies contain cyclooxygenase (COX) enzymes.
- COX enzymes catalyze production of relatively large quantities prostaglandins.
- Prostaglandins are responsible for:
- Producing fever and swelling
- Increasing sensitivity to pain
- Inhibit blood vessel dilation
- Regulate production of acid and mucus in stomach
- Assist kidney function
9 Relief
Aspirin and other NSAID's (non-steroidal anti-inflammatory drugs) are taken to relieve pain and inflammation. Given above, two possibilities:
- Disable Prostaglandins - Since prostaglandins are causing the undesirable effects, stopping these should stop symptoms.
- Disable COX Enzymes - By disabling prostaglandin production at the source, smaller quantities of drug can be used, with same relief from symptoms.
NSAID's act as COX enzyme inhibitors. They bind to these enzymes and
temporarily disable them, stopping prostaglandin function.
10 Aspirin
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11 Prostaglandins
Several different types of prostaglandins, serving many roles. Two classes of COX enzymes are known.
- COX-1 prostaglandins
- Maintain kidney function
- Keep stomach lining intact
- COX-2 prostaglandins
- inflammation
- pain
- fever
Most NSAID's (including aspirin) stop both classes of COX enzymes.
12 COX Enzymes
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| COX-1 Enzyme | COX-2 Enzyme |
Red atoms are a non-selective inhibitor.
13 COX-2 Inhibitor
Celebrex (Celecoxib) structure shown above. Only binds to COX-2 Enzymes
14 Celebrex
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Celebrex is more complicated than aspirin. The extra size and rigid shape make this compound unable to get into the binding site of the COX-1 enzyme.
15 Morphine, Codeine, & Heroin
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16 Morphine and Friends
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| R 1 | R 2 | |
| Morphine | H | H |
| Codeine | CH 3 | H |
| Heroin | CH 3 C(O)- | CH 3 C(O)- |
17 Mode of Action
Morphine, codeine, and heroin have very similar structures.
They also have very similar properties. All are believed to change the pain receptors in the brain. The pain signal is not turned off, but its affect is not ``normal''.
18 Morphine Rule
The following substructure MUST be present:
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19 Related Compounds
Goal: Design a drug with pain-relieving qualities, but without the addiction and other side effects.
Using morphine rule:
- Demerol: Effective pain-reliever.
- Methadone: Used to treat Heroin addiction.
20 Drug Design
- Rarely starts from scratch.
- Relies on structure/function relationships.
- Once promising candidate found, derivatives made to seek ``best'' of the bunch.
- Comparison leads to understanding of necessary and unnecessary structural features.
File translated from TEX by TTH, version 3.02.
On 21 Mar 2002, 11:54.