Term
| What are two sources of histamine? |
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Definition
1. Food and bacteria in GI tract
2. Biosynthesis |
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Term
| How does bacteria metabolism histamine? |
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Definition
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Term
| What is the precursor to histamine regarding its biosynthesis? |
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Definition
Histidine
(has carboxylic acid) |
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Term
| In what tissues is histamine stored where it has a slow turnover rate? |
|
Definition
1. Mast cells
2. Basophils in the blood |
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Term
| In what tissues is histamine found where it has a rapid turnover? |
|
Definition
NOT STORED
Synthesized and metabolized
1. Skin
2. Gastric mucosa
3. CNS |
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Term
| List four ways stored histamine is released |
|
Definition
1. Mechanical means - hammer
2. Antigen - antibody reaction
3. Drugs - morphine whealing @ injection site
4. Snake venom |
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Term
| List four things H1 histamine receptors are resposible for. |
|
Definition
1. Mediate contraction of sm. muscle.
ie. Gut and Bronchi
2. Increase post capillary venule permeability
3. Produce rapid, short lived vasodilation
4. CNS wakefulness |
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Term
| What type of receptor is H1 histamine receptors? |
|
Definition
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Term
| What type of receptor is H1 histamine receptors? |
|
Definition
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Term
| List three things H2 histamine receptors are resposible for. |
|
Definition
1. Stimulate gastric acid secretion
2. Inc. force & rate of heart contraction
3. Cause slow develop, long lasting vasodilation |
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|
Term
| What type of receptor are H2 histamine receptors? |
|
Definition
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Term
| Where are H3 histamine receptors found and what do they do? |
|
Definition
Neural autoreceptors (presynaptic)
Modulate synthesis and release in CNS |
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Term
| Where are H3 histamine receptors found and what do they do? |
|
Definition
Neural autoreceptors (presynaptic)
Modulate synthesis and release in CNS |
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Term
| What two enzymes are involved in histamines metabolisms and is it fast or slow? |
|
Definition
1. Histamine N-Methyl transferase
2. Diamine oxidase
rapid metabolism |
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Term
| What does N-Methyl transferase do to histamine? |
|
Definition
Remove methyl
Then MAO = aldehyde
Then to acid |
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Term
What does diamine oxidase do to histamine?
What special addition can be made? |
|
Definition
Remove basic nitrogen = aldehyde
Then dehydrogenase = acid
SPECIAL ADDITION = can add ribose |
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Term
| Based on the structure of histamine, addition of what increases the SELECTIVITY of H1 agonists? |
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Definition
| Addition of methyl in the 2 position. |
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Term
| Based on the structure of histamine, addition of what increases the SELECTIVITY of H2 agonists? |
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Definition
| Addition of methyl on the 4 position. |
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Term
| What addition to histamine increase the AFFINITY for H3 receptors? |
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Definition
| Addition of a methyl to the alpha position |
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Term
| At physiological pH, is histamine most commonly found as monocation or dication? |
|
Definition
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|
Term
At physiological pH is histamine most commonly found protonated?
What conformation is it most commonly found in when in aqueous solution? |
|
Definition
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Term
What is longest known H1 antag?
Does it have any isomers? |
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Definition
Diphenhydramine.
No isomers. |
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|
Term
SAR for H1 Antags
1. X= C-0 =>
2. X= N =>
3. X= CH => |
|
Definition
1. Ethanolamine or aminoalkyl ethers
2. Ethylenediamine
2 Carbon and 2 Nitrogen
3. Propylamine, alkylamine |
|
|
Term
SAR H1 Antag
Aryl Groups
Give three examples of what aryl group can be. |
|
Definition
1. Phenyl
2. Benzyl
3. Heterocycle
ie. pyridine |
|
|
Term
SAR H1 Antag
Aryl Groups
1. Where can aryl group be substituted?
2. With what?
3. What is effect of substitution? |
|
Definition
1. Para position.
2. Cl, Br, OCH3, etc.
3. Increase lipid solubility and potency, affect biodispostition |
|
|
Term
SAR H1 Antag
Aryl Groups
Where and what type of bonds do aryl groups form with receptor? |
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Definition
| Outside of the histamine receptor and they form hydrophobic bonds which ARE stereospecific. |
|
|
Term
SAR H1 Antag
Aryl Groups
What type of conformation do aryl groups adopt and why? |
|
Definition
| Noncoplanar conformation relative to each other for optimal interaction |
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|
Term
SAR H1 Antag
Aryl Groups
Do aryl groups have similar or differnet binding environments at the receptor? |
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Definition
| Most likely very different binding environments at site of the recptor. |
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|
Term
| Are H1 Antags more or less lipophilic than histamine? |
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Definition
| H1 antag are MORE lipophilic. |
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|
Term
SAR H1 Antag
X to N Distance
1. What is proper distance from X to N?
2. Can they be branched, saturated, unsaturated, or in a ring? |
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Definition
1. Two carbons, three sometimes.
2. Branched = Yes
Saturated = Yes
Unsaturated = Yes
Ring= Yes |
|
|
Term
SAR H1 Antag
N Substitution
1. What usually substituted with?
2. Can it be in a heterocyclic ring?
3. Does stereochemistry matter at this end of molecule? |
|
Definition
1. Must be tertiary
usually dimethyl
2. Yes, can be in hetercyclic ring.
3. Not at this end. |
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|
Term
Physiochemical Properties
H1 Antag
What are free bases usually like? |
|
Definition
| Usually oily and highly lipid soluble. |
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|
Term
Physiochemical Properties
H1 Antag
What are free bases usually like? |
|
Definition
| Usually oily and highly lipid soluble. |
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|
Term
| List four types of metabolism for H1 antags? |
|
Definition
1. N- dealkylation
2. N- oxidation
3. Oxidative deamination
4. Aromatic hydroxylation |
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|
Term
Metabolism of H1 Antag
1. Does metabolism produce active or inactive metabolites?
2. How long is their duration of action?
3. Are any inducers or inhibitors of enzymes? |
|
Definition
1. All inactive.
2. Short, 4 - 6 hours
3. Some are enzyme inducers. |
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