Summary Geneesmiddelen van het endocrien systeem.

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Summary - Geneesmiddelen van het endocrien systeem.

  • 1 College 1: Introduction

  • Endocrine system plays an important role in:
    Autonomic body functions
    Communication between cells and organs
    Endocrine regulation
  • Autonomic body functions
    Functions that are aimed at the continued existence of the individual and the species.
  • Communication between organs and cell systems is important for:
    - autonomic nervous system (relatively quick)
    - hormones (relatively slow)
    - interaction between these systems (neuroendocrine cells)
  • Endocrine regulation examples
    - metabolic functions (energy homeostasis and growth)
    - functioning of the immune system
    - regulation of the internal environment (water homeostasis and electrolyte homeostasis: blood circulation, bone homeostasis)
    - reproduction
  • Types of endocrien regulations
    -Neuronà Quick system (interaction between neuron and target cell, noradrenaline or acetylcholine are the neurotransmitters). 

     -Neuroendocrine hormone àSlow system
    (release in the blood)
  • Endocrine gland hormones are:
    A special type of cells.
  •  Pancreases introduce:
    Insuline and it can work autocrine or paracrine or endocrine. 
  • Autocrine
    Influence the own cell
  • Paracrine
    Influence the neighbor cells
  • Endocrine
    Influence the organ
  • The endocrine system is a system where there is communication between:
    The hypothalamus and the pituitary gland. These releases or inhibit hormones. 
  • Hypothalamus
    Releasing or inhibiting hormones
  • Pituitary gland
    TSH ACTH  FSH
    LH  GH
    MSH  ADH
    Prolactin Oxytocin
  • Adrenal glands
    Glucocorticosteroids
    Mineralocorticosteroids
    Adrenal androgens
  • Thyroid gland
    T3,T4
    Calcitonin
  • Parathyroid glands
    PTH
  • Pancreas
    Insuline 
    Glucagon
  • Ovaries
    Oestradiol
    Progesterone
  • Testes
    Testosterone
  • Peptide hormones and protein hormones
    (membrae receptors)
    Hypothalamus
    Pituitary gland
    Pancreas
    Thyroid glands
    Parathyroid glands
  • Membrane receptors
    -Relatively quick
    -Tyrosine kinase
    -G-protein coupeld receptors (adenylyl cyclase, PI metabolism)
  • Steroid hormones, sterols, thyroxine derivatives
    (Intracellular receptors)
    Adrenal gland
    Reproductive organs
    Calcitriol (vit D derivaten)
    Thyroid gland
  • Intracellular receptors
    -Relatively slow
    -Regulation of protein synthesis (Ligand-gated transcription factors)
  • Thyroid gland T3 and T4 working via:
     
    Intracellular receptors, but are dependent on G-protein coupled receptors(membrane receptors).
  • Endocrine Hormones 
    -Often analogues: stable agonists/antagonists
    (substituted by analogues)
  • Protein hormones = Tropic hormones
    Influence a lot of metabolic parameters in our body.  
    Parentral more stable effector than can be administerd orally. 
    Low bioavailibility via oral.
  • Pharmaceuticals can affect:
    -Hormone synthesis
    -Hormone release
    -Hormone metabolism
  • Bioactive compounds/Hormones
    Metabolically instable--> And thus stable agonist or antagonists are synthesites
  • Effector hormones
    Like anti-diuretic hormones --> Are administered orally. 

    Treatment easier by synthetic steroids and thyroxine derivatives.
  • Hypothalamic-pituitary system
    In the hypothalamus (upper part) are the neuroendocrine cells which synthesise the hormones.

    Released to the bloodstream to the pituitary.
  • Anterior pituitary       (Veins)    front
    Here are endocrine system--> produce hormones
    (these are released to the blood and  act on a specific target organ)
    Hormones from the hypothalamus regulate the release of hormones by the anterior pituitary

    Synthesis of:
    Releasing factors (RF) or hormones (RH)
    Inhibitin factors (IF) or hormones (IH)    
  • Posterior Pituitary   (Arteries)   back
    Green neuroncells in the hypothalamus synthesing posterior pituitary hormones.
    From the left side of the hypothalamus to the right side of the pituitary.

    Here is the production of ADH and oxytocine release. --> directly to the bloodstream.
  • Hypothalamus and Pituitary regulation
    Hypothalamus and pituitary gland together regulate a major part of the endocrine system.
  • Hypothalamus function
    It converts nerve impulses from the brain into a hormonal impulse.
  • Of how many parts is pituitary gland made? And what are they?
    3 parts

    Anterior (anterior lobe)
    Pars intermedia (barely present in humans)
    Posterior (posterior lobe)
  • Neuron cells (purple)
    Neurons synthesing tropic hormones (right of the hyothalamus).
  • TRH
    Thyroid Releasing Hormone
  • CRH
    Corticotropin releasing hormone
  • GHRH
    GHIH
    GrowthHormone Releasinh Hormone
    GrowthHormone Inhibiting Hormone (Somatostatin)

    Released by the hypothalamus--> Act on the interior pituitary --> Force the release of GH in the pituitary. 

      GHRH-->GH-->Liver-->Somatomedins
  • Hormone release scheme
    GH-->Liver-->Somatomedins
    ACTH-->Adrenal cortex-->Glucocorticoids, mineralcorticosteroids, androgens. 
    TSH-->Thyroid-->Thyroxine
    FSH-->Estrogen
    LH-->Estrogen, Progesteron, Testosteron
    Prolactin-->Breast
  • Negative feedback mechanism
    The somatomedins released by the liver can have a negative effect on the release of GHRH in the hypothalamus.
  • ADH
    Anti-Diuretic Hormone1
    In the posterior lobe
    Antidiuretic system is the same as vasopressine 
    Working in the kidney (homeostasis of ion and water.
  • Oxytosine
    Production of the--> Milk
    Contraction of the-->Uterus
    Influence on the-->mooth muscle
  • ADH and Oxytosine work via:
    G-Protein Coupled receptors
  • Hypothalamic hormones
    -Are peptides (except dopamin)

    -Transport to the anterior pituitary is via the bloodstream

    -Neurohormones--> Because their release is regulated by neurons.
  • Hormones Size
    Hypothalamic hormones = Small peptides.
    Pituitary hormones = Large peptides/proteins
  • Action between GH and TSH
    GH down-->TSH down-->(Insulin down, Glucagon down)

    The hormones have influence on the energy load (metabolic load) and growth (depending on the amount of glucose).
    Influence level of glucose and lipids.
  • Anterior pituitary hormone groups
    Group1 Somarotropic hormones
    (GH, Prolactin)
    Species-selective (amino sequence) 
    No binding to sugar

    Group2 Glycoproteins
    LH,FSH, TSH, CG
    Bind to sugar 23-33% of the total structure
    Complex, alfa and beta  chain. 


    Group3 Derived from precursor protein (pro-opiometianocortin)   
    ACTH, alfa-MSH, beta-LPH     
    No sugar like group 1
    Molecular weight MW is the lowest of all gruops
  • Glycoproteins (Group 2)
    Glycoproteins are made up of an alfa-subunit and a beta-subunit. 
    LH,FSH,TSH,CG

    alfa-subunits are virtually identical, contain 2 oligosaccharides chains that are boound via asparagine

    beta-subunits have the specific biological effect and contain 1 or 2 oligosaccharide chains.
  • Pro-opiomelanocortin (Group 3)
    Interesting precursor

    Multiple hormones are produced from a large precursor molecule by enzymatic cleavage (proteases) in various tissues. 


    ACTH and beta-lipotropin are formed in the anterior pituitary

    alfa-MSH is split off in the pituitary pars intermedia (pigmentation).

    a-MSH, B-MSH
    Y-lipotropin,
    B-endorphin and
    are formed in the brain.
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The hypothalamic-pituitary system is characterized by (negative) feedback mechanisms for:
Cortisol
3,5,3-triiodthyronie
Insuline-like Growth Factor-1 (IGF-1)
What are the possible structural changes in theSynthesis to optimise peptide analogues?
  1. ELISION=Shortening the chain by removing an amino acid
  2. INTERCALATION=Lenthening the chain by inserting an amino acid. (increase stability of an alfa helix and particullary beta sheets)
  3. Changing the side chain=Changing an amino acid.
  4. Replacing an L-amino acid by a D-amino acid (the opposite, for the metabolic activity stability)
  5. Blocking an end group.
  6. Replacing S-S bridges by ethylene bridges or by CH2 bonds.

Synthesis of peptide analogues (important)
  • Endogenous peptides are often metabolized quickly.

  • Knowledge of the amino acid sequence and characteristics of a peptide creates oppertunities to develop new analogues with -Increased stability
         -Improved activity
        - Fewer side effects

  • Pharmacological activity of analogues provides insight into the
    structure-activity relationship (SAR)
Example anterior pituitary glycoproteins:
LH
FSH
TSH
Glycoproteins
Bonding of the glucose/sugar part with -NH or -OH of Asn, Ser, Thr, or hydroxy-Lys

Such a protein is usually made up of two chains (alfa and beta subunit) with cysteine amino acids that are connected via disulfide bridges.
Quaternary structure
Determined by association of multiple protein chains.

The final  dimantional  structure of a protein. 
Defining the interaction of the hormone and the biological activity.
Tertiray structure
Establishes through the action of 3 types of forces:
  1. Electrostatic or ionic bonds
  2. Van der Waals force
  3. Hydrogen bonds
These are build up between different amino acids. 



 
Secundary structure a-helices and B-sheets
Alfa helix = Hydrogen bounds between the amino acid gruop and the carboxyl group. (primary structure)
In an a-helix, the C=O group of amino acid n is bound to the N-H group of amine acid n+4 via a hydrogen bond.
Coiled coil structure

Beta-sheets = boundaries between peptides which are characterized by the interaction of hydrophobic course. (give the protein more stabilty and define the biological function of the protein structure and thus hormone structure)  
 Hydrogen bonds between stretched chains
Ant-parallel and Parallel.
Protein structure is devided into 4 structures, which are they?
  1. Primary = Order of amino acids and presence of dissulfide bridges

  2. Secundary = The spontaneous folding of certain regions during synthesis, leading to the formation of a-helix or B-sheets
    First dimention 

  3. Teritary = Spatial organization of regions located far apart, such as combinations of helices and sheets
    (complete chain structure
    The importance of the biological activity 

  4. Quanternary = Spatial organization in proteins with multiple peptide chains 

    Protein structure is mainly determined by the side chains in the amino acids

Acidic amino acids
  1. Aspartate
  2. Glutamate