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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
Q

Glucocorticoid Biosynthesis

A
  • Occurs in Zona Fasciculata
    • ​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
Q

Glucocorticoid Pathway

Photo

A

Occurs in teh Zona Fasciculata

27
Q

Androgen Biosynthesis

A
  • Occurs @ Zona Reticularis
    • ​lacks significant 21-hydroxylase expression
      • ​can not produce
        • mineralcorticoids or corticosteroids
  • ​​​Main product is DHEA -> Androsteneidone
    • which becomes Testosterone / Androgen
      • in peripheral issue
28
Q

P450scc

CYP11A1

A

Cholesterol Side Chain Cleavage Enzyme

considered a Lyase

Cholesterol -> Pregnenolone

@Mitochondria

inhibited by AMINOGLUTETHIMIDE

29
Q

Aminoglutethimide main function

A

​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
Q

Aminoglutethimide

at Low Dose

A

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
Q

Trilostane

A

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
Q

Ketoconazole

A

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
Q

Metyrapone

Etomidate

A

Steroid Enzyme inhibitor

Corticosteroid Inhibitor

  • Inhibits 11B-Hydroxylase (CYP11B1) @ ER
    • ​–/–> Cortisol
      • ​final step of corticosteroid synthesis
34
Q

Aldosterone Synthase Inhibitors

A

Still in Development

Fadrozole / 3 other products in development

35
Q

Spironolactone

A

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 issues with males
36
Q

Eplerenone

A

Mineralocorticoid Receptor Competitive Antagonist

@ Distal tubule cells of Kidney

Diuretic for Hypertention

  • Comapared to Spiranolactone,
    • it REDUCES its binding to:
      • Androgen/Progestrone Receptor
37
Q

Mifepristone

A

Glucocorticoid Receptor Antagonist

for Cushing’s Syndrome

  • also a Progestrone Receptor Antagonist*
  • an Abortion Pill*
38
Q

Mitotane

A

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
Q

Adrenocorticoid Metabolism

A

Reduction / HSD / Side chain Cleavage

40
Q

Glucocorticoid Receptor

A

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
Q

CortiSOL (Hydrocortisone)

vs

Cortisone

A

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
Q

Mineralcorticoid Receptor

A

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
Q

Nuclear Binding Domains

A
  • 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
Q

How do Mineralcorticoids overcome the

10FOLD difference in concentration vs Glucocorticoids??

0.05-0.20 vs 40-180 ug/ml

A
  • 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
Q

Insertion of bulky substituents** on the **β-side of the steroid does?

A

Abolishes

GLUCOCORTICOID ACTIVITY

no activity on mineralcorticoid activity

46
Q

Insertion of bulky substituents on the α-side of the steroid does?

A

Does NOT abolish Glucocorticoid Activity

Significantly impairs

Mineralcorticoid Activity

47
Q

Structure-Activity Relationship

Amoung Adrenocorticoids

A

C & D Rings

Esp Carbons 11-21 (except 14/15/19)

Are most important for receptor Binding

48
Q

3 Major Groups of Adrenal Steroids / Drugs

classified by Biological activities

A
  • 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
Q

Deoxycorticosterone

A

Natural MC, substrate for Aldosterone Synthase

Moderate MC Activity

no GC activity

  • 1st synthesized corticosteroid
    • in 1937, Nobel Prize
    • Tadeusz Reichstein
50
Q

Fludrocortisone

A

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
Q

Cortisol (Hydrocortisone) & Cortisone

A

Glucocorticoid w/ Moderate-Low Salt retention

Some Anti-Inflammatory activity

  • much less inflammatory activity than 1-ene forms*
  • prednisolone / prednisone*
52
Q

Prednisolone & Prednisone

A

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
Q

Δ corticoid’s Orientation & Metabolism

A
  • 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
Q

Methylprednisolone

A

GlucoCorticoid w/ very little - NO salt retention

Inhibits CYP oxidation @ C6

6a-methyl decreases salt retention

55
Q

Dexamethasone / Betamethasone

Traimcinolone / Beclomethasone

A

Glucocorticoid w/ very little - NO salt retention

Anti-Inflammatory

16-OH / 16-methyl helps eliminate salt retention

9a-F/Cl INCREASES Glucocorticoid Activity

56
Q

16 a - OH

16a/b - methyl

6a - methyl

A

Substituants on steroids that:

DECREASE SALT RETENTION

ex: methylprednisolone / other GC w/ little to no salt retention

triamcinalone / betamethasone

57
Q

1 - ene (double bond)

9a - F / Cl

A

Substituents on steroids that:

Increase BOTH Glucocorticoids & Mineralcorticoid activity

58
Q

Numbering Primary Steroids

59
Q

Glucocorticoid pharmacological effects of

BLOCKING inflammatory / immune response

A
  • 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

PDAT2 (22 decks)

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