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PDAT2 > Lec 4/5 Adrenal MedChem > Flashcards

Lec 4/5 Adrenal MedChem Flashcards

1
Q

Adrenal Medulla

A
  • Can survive without it
  • Secretes Catecholamines:
    • Epinephrine / Norepinephrine
      • from tyrosine
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2
Q

Adrenal Cortex

A
  • Essential for LIFE
    • ​G - F - R
  • Z. Glomerulosa:
    • Mineralcorticoid = Aldosterone
  • Z. Fasciculata:
    • Glucocorticoid = Cortisol
  • Z. Reticularis (innermost)
    • Androgens
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3
Q

Zona Glomerulosa

A
  • Grape-like Cluster of cells
  • OUTER MOST
  • Secretes Mineralcorticoids
    • Aldosterone
      • Controlled by Renin-Angiotensin
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4
Q

Zona Fasciculata

A
  • Cells in Rows or Cords
    • Fat droplets in cells, seperated by Capillaries
  • ​Cholesterol is stored here
  • Secretes Glucocorticoids:
    • ​Cortisol
      • ​controlled by ACTH
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5
Q

Zona Reticularis

A
  • Network of branching small / dark cells
  • Secretes Androgens
    • ​controlled by ACTH
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6
Q

Cortisol Secretion Pathway

A
  • Stressors / Diurnal Rhythem -> Hypothalamus
    • -> CRH = corticotropin releasing hormone
      • -> Pituitary
        • -> ACTH -> Adrenals
          • CORTISOL
  • Cortisol Negative Feedback to Pituitary & Hypothalmus
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7
Q

Adrenocorticoids

= Corticosteroids

A

Adrenal Cortex Steroids

aka Corticosteroids

Mineralcorticoids + Glucocorticoids

Androgens

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8
Q

Glucocorticoids

A

Cortisol = Hydrocortisone

From Adrenal CORTEX

  • Essential for LIFE
  • ​Effects are Permissive
    • not directly responsible for the activity
      • but NECESSARY for FULL EXPRESSION
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9
Q

Glucocorticoid = Cortisol

METABOLIC effects

A
  • Carbohydrate Metabolism
    • ​INCREASE supply of glucose
      • gluconeogenesis
  • Protein Metabolism
    • ​Reduce utilization of AA’s for the formation of protein
  • Fat Metabolism
    • ​INCREASE mobilization of FA’s / Glycerol from adipose tissue
      • to undergo gluconeogenesis
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10
Q

Primary Steroids

A
  • 5a-Cholestane
  • 5a-Estrane
  • 5a - Androstane
    • ​-> ANDROGENS
  • 5a - Pregnane
    • ​-> Mineralcorticoids / Glucocorticoids
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11
Q

Naming & Numbering Cholesterol Structure

A

Alpha = AWAY from plane

Beta = Above / outwards

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12
Q

Sterene Ring Configuration

A

Sterene rings assume Chair Configuration

  • Changing the stereochemistry of the BACKBONE carbons
    • greatly change the steroid SHAPE
      • 5-Beta -> PREVENTS BINDING
        • no activity
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13
Q

StAR Protein

A

Rate LIMITING step in Steroid Biosynthesis

Transports Cholesterol

Cytosol -> Mitochondria

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14
Q

Steroid Biosynthesis Pathway Image

A
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15
Q

Second Messengers

in Steroid BioSynthesis Pathway

A

All very Small & Lipophylic

Diffuse very Quickly!

  • cAMP​
    • -> Activates PKA
  • DAG
    • ​-> Activates PKC
  • IP3
    • ​-> Opens Ca2+ channels in ER
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16
Q

Slow Response

in Steroid BioSynthesis Pathway

A
  • ACTH -> GPCRreceptor
    • -> Adenyl Cyclase -> cAMP released
      • -> Activate/phosphorylate PKA
        • -> enter the nucleus
          • ​Nuclear Receptor bound C
          • Activate Transcription of Steroids
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17
Q

Cholesterol -> Pregnenolone

A

Occurs in the Cytosol -> Mitochondria

StAR Protein does this transportation

LYASE

once it enters the Mito -> it is then

DEDICATED to be an Adrenal Hormone

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18
Q

Lyase

(Desmolase)

A

Catalyzes cleaveavage of a Carbon-Carbon Bond

in a substrate w/ formation of 2 products by

a process other than HYDROLYSIS

ex. Oxidoreductase / Transferase

Desmolase = Specific to Steroid Synthesis

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19
Q

Hydroxylase

A

Add or Remove a HYDROXYL MOIETY

Adds -OH

Removes -OH

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20
Q

Hydroxysteroid Dehydrogenase

HSD

A

Alcohol Oxidoreductase

Non-CYP Enzyme

=O to -OH

and the reverse

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21
Q

Reactions that occur in the MITOchondria

A

Cholesterol - lyase -> Pregnenolone

Deoxycorticosterone - aldosterone synthase -> Aldosterone

11-Deoxycortisol -Hydroxylase -> Cortisol

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22
Q

Mineralcorticoid Biosynthesis

A
  • Occurs in the Zona Glomerulosa
    • ​lacks P450c17 expression
      • ​= Prognenolone –/–> Hydroxypregnenolone or DHEA
      • ​so can not become glucocorticoid or androgen
  • ​​Can continue to become Progestrone -> Aldosterone
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23
Q

Mineralcorticoid Biosynthesis Pathway

Photo

A

Occurs in Zona Glomerulosa

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24
Q

Mineralcorticoid Pathway

A
  • Cholesterol - Lyase -> Pregnenolone
    • HSD -> Progesterone
      • Hydroxylase -> deoxycorticosterone
        • ​​Aldosterone Synthase -> ALDOSTERONE
  • ​​​Occurs in Zona Glomerulosa
25
**Glucocorticoid Biosynthesis**
* Occurs in _Zona **F**asciculata_ * ​**P450c17** has impaired ***Lyase Activity (17-20-lyase)*** * ​so **Androgen synthesis is MINOR** * ​*Lacks **Aldosterone Synthase** expression* * *​so it can NOT synthesize **Mineralcorticoids*** * = *aldosterone* * *​​​***_Main product is CORTISOL_**
26
**Glucocorticoid Pathway** **Photo**
Occurs in teh Zona **Fasciculata**
27
**Androgen Biosynthesis**
* Occurs @ _Zona **R**eticularis_ * ​*lacks significant **21-hydroxylase** expression* * *​can not produce* * ***mineralcorticoids or corticosteroids*** * ***​​​***Main product is **DHEA -\>** **_Androsteneidone_** * which becomes **Testosterone / Androgen** * in _peripheral issue_
28
**P450scc** CYP11A1
**_Cholesterol Side Chain Cleavage Enzyme_** considered a **Lyase** Cholesterol -\> Pregnenolone _@Mitochondria_ *inhibited by **AMINOGLUTETHIMIDE***
29
**Aminoglutethimide main function**
​At HIGH Dose --\> for **Cushings Syndrome** * *Inhibits **Cholesterol side Chain Cleavage*** * **​=** P450scc = CYP11A1 @**_Mitochondria_** * **_​_**Blocks the **FIRST STEP** * so it controls the production of ***CORTICOSTEROIDS*** * **_DEADLY_** since you need cortex to survive
30
**Aminoglutethimide** at Low Dose
Low dose = for **Breast Cancer etc.** * *Inhibits **AROMATASE** (CYP19) in* **_Peripheral tissues_** * _Fat / Liver / Tumor_ * **Androstenedione / Testosterone** from _Z. Reticularis_ * *conversion to **Estrone / 17B-Estradiol*** *is inhibited*
31
**Trilostane**
For **Cushing's Disease in DOGS** *and possibly Breast/Prostate cancer* * Very structurally similar to **progestrone** * *Competitively Inhibits **3B- HSD** (hydroxysteroid dehydrogenase)* * ***​*2nd tier inhibition of all 3 pathways** * -/-\> progestrone / androstenedione
32
**Ketoconazole**
Antifungal agent Second line therapy for **Castration resistant prostate Cancer** * MAJOR inhibition of **17,20-Lyase** * 3rd column steps producing **Androstenedione / DHEA** * **​***Minor inhibition of **17A & 11B - Hydroxylase*** * 2nd column steps * Final tier step to ***Aldosterone / Cortisol***
33
**Metyrapone** **Etomidate**
Steroid Enzyme inhibitor ***Corticosteroid Inhibitor*** * Inhibits **11B-Hydroxylase** (CYP11B1) @ **_ER_** * **_​_***--/--\> **Cortisol*** * ​final step of corticosteroid synthesis
34
**Aldosterone Synthase Inhibitors**
***Still in Development*** Fadrozole / 3 other products in development
35
**Spironolactone**
**Mineralcorticoid Receptor Competitive Antagonist** ​@ _Distal Tubule cells of KIDNEY_ * Potent **Diuretic** activity --\> for **Hypertention** * *Side effects:* * also stimulates **Progestrone** receptor * *inhibits **Androgen** receptor* * ​**ED / Erectile issue**s with males
36
**Eplerenone**
**Mineralocorticoid Receptor Competitive Antagonist** @ _Distal tubule cells of Kidney_ **Diuretic** for **Hypertention** * Comapared to Spiranolactone, * *it REDUCES its binding to:* * ***Androgen/Progestrone Receptor***
37
**Mifepristone**
**Glucocorticoid Receptor Antagonist** for **Cushing's Syndrome** * also a **Progestrone Receptor Antagonist*** * an **Abortion Pill***
38
**Mitotane**
**Inhibits STEROID Biosynthesis** **Destroys MITO** @ _Ad Cortex_ palliative treatment of **_Adrenocortical Carcinoma_** * Requires **metabolic activation** by the _adrenal gland_ * Discovered from DDD / DDT insecticides
39
**Adrenocorticoid Metabolism**
**Reduction / HSD / Side chain Cleavage**
40
**Glucocorticoid Receptor**
**Ligand-Activated Ranscription Factors** _Expressed in MANY TISSUES_ * Easily crosses the membrane (LIPOPHILIC) * Binding domain is normally ***INHIBITED*** (bound by inhibitor) * Hormone/**Cortisol** --\> RELEASES the inhibitor * _enters the nucleus_ * --\> **Transcription occurs**​
41
**CortiSOL** (Hydrocortisone) vs **Cortisone**
**Cortisone = *Less Active Metabolite*** Also it has *NO activity on the **mineralcorticoid receptor*** **11B-HSD** converts between the two *but* ***Cortisone --/--\> CortiSOL*** *in* ***_Kidney_***
42
**Mineralcorticoid Receptor**
**Ligand-Activated Ranscription Factors** _Limited expression to_ **_Kidney / Colon / Salivary/Sweat Glands / Hippocampus_** * Easily crosses the membrane (LIPOPHILIC) * Binding domain is normally ***INHIBITED*** (bound by inhibitor) * Hormone/**Aldosterone** --\> RELEASES the inhibitor * _enters the nucleus_ * --\> **Transcription occurs**​
43
**Nuclear Binding Domains**
* Most DNA response elements for Nuclear receptors are **_almost exactly the same_** * for Estrogen/Progestrone/Glucocorticoid/Thyroxine receptors * Differences for recognition are from: * **opposite reading direction** * **_Amount of Nucleotides that seperate_** * **3-5 bases in BETWEEN** * make the BIGGEST DIFFERENCE in translation
44
How do **Mineralcorticoids** overcome the **10FOLD difference in concentration vs** **Glucocorticoids??** 0.05-0.20 vs 40-180 ug/ml
* **Cortisone** (less active GC than CortiSOL): * has *NO activity on the **mineralcorticoid receptor*** * also *does **NOT** convert back to **CortiSOL** in the _KIDNEY_* * ​no TYPE 2 of 11B-HSD unlike the liver
45
Insertion of **_bulky substituents**_ on the _**β-side_** of the steroid does**?**
**Abolishes** ***GLUCOCORTICOID ACTIVITY*** *no activity on mineralcorticoid activity*
46
Insertion of **_bulky substituents_** on the **_α-side_** of the steroid does?
*Does NOT abolish Glucocorticoid Activity* **Significantly impairs** ***Mineralcorticoid Activity***
47
**Structure-Activity Relationship** **Amoung Adrenocorticoids**
**C & D Rings** Esp Carbons 11-21 (except 14/15/19) **Are most important for receptor Binding**
48
**3 Major Groups of Adrenal Steroids / Drugs** classified by Biological activities
* **Mineralcorticoids** (aldosterone) * Deoxycorticosterone * Fludrocortisone * **_Glucocorticoids w/ moderate to low salt retention_** * _**​**Prednisolone / Prednisone_ * _Cortisone / Hydrocortisone_ * **Glucocorticoids w/ *little or no salt retention*** * ***​****Methylprednisolone* * *Dexamethasone / Betamethasone* * *Triamcinolone*
49
**Deoxycorticosterone**
Natural MC, substrate for **Aldosterone Synthase** **Moderate MC Activity** *no GC activity* * 1st synthesized corticosteroid * in 1937, Nobel Prize * Tadeusz Reichstein
50
**Fludrocortisone**
HIGH salt retention, **oral for Addison's Disease** ***Topical Antiinflammatory*** Class = **MC** * Halogen Inductive effect: * **Potent MC Activity (800x)** * *some GC activity (10x)* * Prevents metabolix oxidation of **11B-OH**
51
**Cortisol (Hydrocortisone) & Cortisone**
_**Glucocorticoid** w/ Moderate-Low Salt retention_ ***Some Anti-Inflammatory activity*** * much less inflammatory activity than 1-ene forms* * prednisolone / prednisone*
52
**Prednisolone & Prednisone**
**Δ corticoids** for treatment of **Rheumatoid Arthritis** _**GC** w/ Moderate-low salt retention_ **4X more Anti-Inflammatory activity** vs Cortisol/cortisone * little more salt retention as well* * **1-ene** form of Cortisol/cortisone
53
**Δ corticoid's Orientation & Metabolism**
* Glucocorticoid Receptor prefers / Increased activity: * **Flattened Boat \>** half-chair * on the A-Ring * **Prednisolone** is the active form, metabolized 3 ways: * *20-Hydroxyprednisolone* * *inactive, **MAJOR pathway*** * *​**6B-Hydroxyprednisolone* * **16a-Hydroxyprednisolone** * **​actually MORE ACTIVE** (like a pro-drug)
54
**Methylprednisolone**
**GlucoCorticoid** w/ *very little - NO salt retention* ## Footnote **Inhibits CYP oxidation @ C6** ***6a-methyl decreases salt retention***
55
**Dexamethasone / Betamethasone** **Traimcinolone / Beclomethasone**
**Glucocorticoid** w/ *very little - NO salt retention* **Anti-Inflammatory** ***16-OH / 16-methyl** helps eliminate salt retention* **_9a-F/Cl INCREASES Glucocorticoid Activity_**
56
**16 a - OH** **16a/b - methyl** **6a - methyl**
Substituants on steroids that: ***DECREASE SALT RETENTION*** ex: methylprednisolone / other GC w/ little to no salt retention triamcinalone / betamethasone
57
**1 - ene (double bond)** **9a - F / Cl**
Substituents on steroids that: ## Footnote **Increase BOTH Glucocorticoids & Mineralcorticoid activity**
58
**Numbering Primary Steroids**
59
**Glucocorticoid pharmacological effects of** **_BLOCKING_ inflammatory / immune response**
* Decrease ***permeability of capillaries*** - allowing less plasma and fewer lymphocytes to enter injured areas * Depression of ***phagocytosis by white blood cells*** * Suppression of ***thymus-derived lymphocytes*** * Suppression of ***key enzymes (e.g., interleukin-1) necessary for inflammatory response***

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