Med Chem Lectures 3 and 4
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- ACTH is cleaved from
- POMC
- "ups your steroids, gives you some pigment, thins you down, and makes you feel good"
- POMC
- stimulates release of ACTH
- Physical or emotional stress
- increases glucocorticoid production by the adrenal gland
- ACTH
- act on gonads to inhibit stimulation by estrogen or testosterone
- Glucocorticoids
- Increased __ feedback to the hypothalamus decreases GnRH secretion, which in turn leads to lower secretion of LH
- β-endorphin
- leads to decreased fertility in both men and women.
- Low LH
- is equivalent to stress and can result in amenorea or in anovulation
- extensive exercise
- regulates steroid synthesis (rather than secretion) by the Adrenal Cortex.
- ACTH
- ACTH promotes the “fight or flight†response by stimulating synthesis of:
- glucocorticoids, mineralcoritcoids, and androgen precursors
-
increase glucose production, inhibit
protein synthesis, increase protein breakdown stimulate lipolysis,
and turn down the immune response - Glucocorticoids, such as cortisol and hydrocortisone
- promote water retention and thereby increase blood volume and blood pressure
- Mineralcorticoids, such as aldosterone
- provide hormones such as testosterone, which may help provide an increased aggressive attitude to cope with the stress
- Androgen precursors
- Too much ACTH leads to
- Cushing’s disease
- leading endogenous cause of Cushing’s disease:
- benign pituitary adenoma (70%)
- Endogenous causes of Cushing’s disease
-
tumors (30%)
benign pituitary adenoma (70%) - Exogenous cause of Cushing's disease:
- OD of ingested corticosteroids (most common cause of the disease)
- Too little ACTH leads to symptoms of
- Addison’s disease
- Addison’s disease itself is the result of a “primary†loss of function of the
- adrenal gland
- drug formulation of ACTH, Acthar = a brand name
- Corticotropin
-
limited use to decrease immune system
function; been used to alleviate exacerbations of multiple sclerosis and
myasthenia gravis - corticotropin
- cheaper to make than the 39 AA full length ACTH corticotrpin
- Cosyntropin (cortrosyn) = 24 AA synthetic peptide
-
If the body makes little or nothing
of some normally endogenous peptide, when that peptide is administered exogenously... - the body’s immune system mounts an immune response against it, which may present as an allergic reaction.
- primary use of Cosyntropin
- diagnostic, (short half-life)
- LH and FSH are from the
- pituitary
- Human chorionic gonadotropin (hCG) is from the
- PLACENTA
- LH, FSH, and HcG are composed of
- two peptide chains (subunits) alpha and beta
- all of the 3 gonadotropins have two subunits, the alpha subunit has __ AA's and
- 92; identical for all three
- specificity of gonadotropins is conferred by the __ subunits
- beta
- The homology between the first 115 AA in the beta chains of gonadotropins LH and CG is __ .
- 82%
- The alpha and beta chains of gonadoptropins interact with each other by __ interactions, with NO inter-chain S-S bridges.
- ionic and hydrophobic
-
Both subunits of the are __
glycosylated (sugar residues contribute between 16% and 30% of the total mass of the hormones). - gonadotropins
- Two main functions of the carbohydrate (the glycosylated portion of the gonadotropin)
- RECOGNITION and STABILITY
- removal of one of the three carbohydrate groups in __ (beta chain has 2; alpha chain has 1) reduces half-life from 90 minutes down to 2-3 minutes.
- FSH
- what type of affinity do gonadotropins have for their receptors?
- very high
-
To achieve half of the maximum
response, only 1% of the receptors need to be occupied. - gonadotropins
- occurs by endocytosis or decreased rates of synthesis, or both mechanisms
- receptors become desensitized
- Promotes development and maturation of ovarian follicles
- FSH
- Stimulates ESTROGEN synthesis and secretion by the ovarian follicles
- FSH
- Stimulates maturation of sperm and testicular development
- FSH
-
contributes to the final maturation and development of both the
follicle and the ovum that it contains. - LH
- Promotes conversion of the ruptured follicle to become a corpus luteum
- LH
- produces its own estrogen and subsequently progesterone.
- corpus luteum
-
Progesterone exerts negative feedback on the __ to decrease the production of LH and thus prevent further follicle and ovum development until progesterone levels subside at
the end of the menstrual cycle. - pituitary (and hypothalamus)
- If no positive stimulus to the corpus luteum is received from placental hCG within 7 days, the corpus luteum begins to __.
- shrink and degenerate
- Re-initiation of the menstrual cycle occurs because low levels of estrogen and progesterone stimulate
- the hypothalamus to increase secretion of GnRH
- increased GnRH stimulates the anterior pituitary to release increased amounts of __.
- FSH and LH
- stimulates synthesis and secretion of androgens, especially testosterone, by the testes
- LH
- when pregnancy occurs ( >7 days after ovulation) __ stimulates the ovarian corpus luteum to secrete high levels of estrogen and progesterone
- CG
- Therapeutic use of CG
- stimulates ovulation
- a 1:1 ratio of FSH and LH, following their purification from the urine of postmenopausal women, called “menotropinsâ€
- Pergonal
- Usage of Pergonal in women
- admin for 7-12 days to promote growth of the ovarian follicle to enhance fertility
- Pergonal works only if women don’t produce adequate levels __ of on their own.
- FSH/LH
- hCG must be administered once the __ in order to induce ovulation and permit pregnancy.
- follicles are mature
-
Administered for at least 3 months to induce spermatogenesis for men
who don’t produce sufficient gonadotropins - Pergonal
- it is FSH ONLY, purified from urine of postmenopausal women
- Fertinex
- Urofollitropin is aka
- Fertinex
-
Administered early in the follicular phase to promote follicle development,
especially for women who ovulate but whose fallopian tubes are too narrow to allow the egg to pass. - Fertinex
- It is also used for women with polycystic ovary syndrome (PCOS), where ovaries are enlarged, but follicles remain very small. Often used for in vitro fertilization.
- Fertinex
-
a synthetic FSH (so no trace amounts of LH are possible). Tends to have a
relatively low pH (acidic). - Follintropin-alpha
-
For males, can be used
if the testes are OK, but pituitary secretion of gonadotropins is inadequate. - Follitropin-alpha
-
a synthetic FSH, but with a different pattern of sugars so it has a higher
pH. - Follitropin-beta
- Profasi, Pregnyl
- CG
- Purified from the urine of pregnant women.
- CG
- Administered to stimulate ovulation in women who lack function in their anterior pituitary and cannot secrete LH.
- CG
- can also be used for cases of hypogonadism (insufficient development of the reproductive organs).
- CG
- If the reproductive problem is due to pituitary dysfunction, this condition may be called
- "hypogonadotrophic hypogonadism"
- where during childhood the testicles don’t descend into the scrotum.
- “cryptorchidismâ€
- Choriogonadotropin alpha is aka
- Ovridel
- This is the recombinant DNA product identical to hCG, which is now becoming less costly to obtain relative to purifying hCG from urine.
- Ovridel
-
these hormones are synthesized in the
hypothalamus and then moved along the neuronal axons to the posterior pituitary cells - ADH and oxytocin
-
Each chain has a carbohydrate side
chain coupled through AA Asparagine (Asn). - TSH
- sugar function
- stability and recognition
-
Diagnostic, to determine whether a thyroid problem is primarily at the thyroid itself
or whether the problem is with the pituitary gland. - TSH
- treatment of hypothyroidism if the thyroid is causing the problem
- direct admin of t3 or t4 (thyroxin) - TSH admin would not increase thyroxin
- in secondary hypothyroidism the primary defect is at the
- anterior pituitary
- treatment for secondary hypothyroidism
- admin of TSH to increase the release of thyroxine
-
to rule out a tertiary hypothyroidism, TRH could be given to determine whether
TSH is secreted from the __. - pituitary
- helps the kidneys retain water, in order to control the osmolarity of the blood
- ADH
-
at high concentrations, __ causes arterioles and capillaries to contract (especially coronary vessels),
which increases local blood pressure - ADH
- ADH is aka
- vasopressin
- defined by the concentration of ligand required for occupancy at equilibrium of half of the available receptors
- receptor AFFINITY
- corresponds to a very low number, such as picomolar,
- high affinity
- corresponds to a higher number, such as micromolar or millimolar
- low affinity
- is NOT recommended for treating low blood pressure, since it affects coronary vessels
- vasopressin
- how to treat hypotension
- increase peripheral resistance; do not work directly on the heart because of the corresponding stress
- stimulates muscles in the uterus to contract
- Oxytocin
-
This hormone is secreted during
labor to cause delivery of the fetus - oxytocin
-
stimulates contraction of smooth muscle in the mammary
glands, which causes milk to be squeezed out of the alveoli (small sacs) so it can enter larger cavities
(sinuses) for release to the baby. - oxytocin
- __ causes alveoli to fill (let-down), whereas __ causes alveoli to empty (secretion)
- prolactin, oxytocin
- These two hormones each consist of 9 AA
- oxytocin and ADH
- both hormones have their C-terminal AA blocked by amidation (CONH2).
- ADH and oxytocin
- has Phe 3 and Arg 8
- ADH
- has Ile 3 and Leu 8
- Oxytocin
- both ADH and oxytocin have this residue at position 2
- Tyr
- Steric hinderance indicates that receptors for ADH and oxytocin are similar in the region that will recognize Tyr 2, but different in the region that will recognize
- positon 3
- synthetic form of ADH with Arg replaced with Lys
- Lypressin
- Pintocin is aka
- oxytocin
-
a synthetic peptide given only with strict medical supervision (in a
hospital) to induce labor/delivery - oxytocin
- It can also be used to speed up the delivery of the placenta following delivery of a baby.
- oxytocin
- a synthetic peptide that can be given as a nasal spray. It is used to treat a form of diabetes called diabetes insipidus
- Lypressin
-
where pituitary release of ADH
doesn’t occur properly, resulting in the loss of water retention, extreme thirst, and dehydration - “diabetes insipidusâ€
-
a synthetic peptide that can also be given as a nasal spray, or orally, or
parenterally. It is also used to treat the symptoms of diabetes insipidus - Desmopressin
-
used to treat children who
experience uncontrolled bed-wetting. - Desmopressin
- It differs structurally from ADH in that the N-terminal amino group of Cys 1 has been removed, and the L-Arg 8 has been replaced with a D-Arg
- Desmopresin
- The structural abbreviation is dDAVP
- desmopressin
- lypressin with three Gly AA’s coupled in front of N-terminal Cys 1
- terlipressin
- It is given to treat bleeding of the esophagus that may result from cirrhosis of the liver.
- Terlipressin
- posterior pituitary hormones
- oxytocin and ADH
- two main hormones secreted by the thyroid gland
- t3 (tri) and t4 (thyroxine)
- a segment of a large protein called thyroglobulin
- Thyronine
- Main component of thyriod gland =
- follicles
-
is like a bag of
grapes (acinar = Latin for “grapeâ€), with each grape being a follicle. - Thyroid
- Promote release of T4 and T3 from thyroid gland
- TSH
- Stimulate uptake of iodide (I - ) from blood into acinar cells.
- TSH
-
Even under normal conditions, __ is pumped into the cells against a 20:1 concentration
gradient. - iodide
- Under excess __ stimulation, iodide can enter against a gradient > 100:1.
- TSH
- Enzyme that puts iodide onto tyrosine =
- thyroid peroxidase
- requires H2O2 as a cofactor; so named because it gets energy for aromatic halogenation by cleaving peroxide
- thyroid peroxidase
- Since __ are quite insoluble, to move through the circulation, they adsorb to one or more of three plasma proteins
- T4 and T3
- carries about 3/4 of all T4 and T3
- Thyroxin-binding globulin
- also called T4–binding pre-albumin
- Transthyretin
- It has an affinity 1000 times less affinity for T4 than thyroxin-binding globulin
- transthyretin
- caries only 10% of T4, but about 30% of T3
- Albumin
- has four identical subunits with a funnel-shaped opening at one end
- Transthyretin
- Principal receptors for t3 and t4 are here
- in nucleus of cells
- MSH, ACTH, LPH, and endorphins are all prodcuts of the enzymatic cleavage of
- POMC
- the primary reason why drugs that mimic CRH have not been developed
- the diversity of the peptide products derived from the enzymatic cleavage of POMC - (and their many functions)
- ACTH and b-endorphins act on different pathways to
- diminish fertility
- inhibit GnRH release and CRH release as well
- estrogens
- inhibition of GnRH by estrogen is this type of response
- stress
- lowered CRH release by estrogens is
- diminished POMC processing and thereby lower ACTH and b-endorphin secretion
- the reasoning behind use of corticotropin for autoimmune disease over more powerful steroidal drugs which provide faster relief
- more ADRS
- in females, LH
- induces ovulation
- once there is a sharp increase in estrogen, about a day later, there is a simultaneous release of FSH and LH from the AP which
- promote the rupture of the follicle and the release of the ova
- with promoting by LH, this later becomes the corpus luteum
- the ruptured follice which releases the ova
- the loss costly analog of hCG which has the same applications
- ovridel
-
Similar to the gonadotropins, __ has two peptide subunits held
together by noncovalent (ionic and hydrophobic) interactions. - TSH
- Each chain of TSH has a carbohydrate side chain coupled through this AA
- Asparagine (Asn)
- admin product of TSH
- TSH
- If the primary defect causing hypothyroidism is in the thyroid, treat with
- direct admin of T3 / T4 (thyroxine)
- if the primary defect is at the anterior pituitary (secondary hypothyroidism), treat with
- admin of TSH
- enhances release of thyroxine
- TSH
- to rule out a tertiary hypothyroidism, __ could be given to determine whether __ is secreted from the pituitary.
- TRH, TSH
- two hormones released from the PP
- ADH and oxytocin
- since vasopressin activity occurs only at high concentrations, this suggests
- different affinities by different target cells for the ADH
- both form a ring by virtue of S-S bridge btw CYS residues at positions 1 and 6
- ADH and Oxytocin
- convulsions which accompany pregnancy-induced hypertension (a leading cause of death to mother or child in underdeveloped countries)
- eclampsia
-
formed by the conjugation of two diiodinated
(or one di- and one mono-iodinated) tyrosine residues within thyroglobulin - thyronine
- Main component of gland = follicles
- thyroid
- are secreted into the lumen for storage of hormone precursors
- thyroglobulin and hypoiodic acid
- When more thyroid hormones are needed by the body, __ carrying the hormones is pulled back into the cell at this surface by endocytosis
- thyroglobulin
- must occur before thyroid hormones are secreted into the bloodstream for transport
- thyroid hormones must be chopped off of thyroglobulin
- About one-third of the total weight of the whole thyroid gland is due just to the amount of
- thyroglobulin
- Stimulate uptake of iodide (I-) from blood into acinar cells.
- TSH
- Under excess __ stimulation, iodide can enter against a gradient > 100:1
- TSH
- Enzyme that puts iodide onto tyrosine
- thyroid peroxidase
- requires H2O2 as a cofactor
- thyroid peroxidase
-
Iodine enters the lumen of the
follicle as - HOI or EOI
- Its other function is to couple either two DIT’s or a DIT and an MIT to form Tg-bound T4 or T3
- thyroid peroxidase
- From a single Tg molecule, only __ hormones are released.
- 2 to 5
- Since T4 and T3 are quite insoluble, to move through the circulation, they
-
adsorb to one or more of three
plasma proteins - Even with a bound T4, transthyretin also binds
- four molecules of Vitamin A
-
About 80% of T3 __
comes from in the peripheral tissues (especially liver and kidney). - removal of iodide from T4
- it only carries one of the hormones (T4)
- Transthyretin
- Principal T3 / T4 receptors are here
- in nucleus of cells
- The main result of thyroid hormones binding to nuclear receptor proteins is to
- stimulate transcription of a variety of genes, resulting in increased production of proteins.
-
lack of hormone from thyroid causes increased release of TSH, that
stimulates the thyroid to enlarge in an effort to compensate - “Non-toxic†Goiter
- may be due to lack of I2 in diet
- non-toxic goiter
-
A lack of iodine during early childhood means lack of CNS development (mental
retardation) and a stunting of growth due to abnormal bone formation - Cretinism
-
Lack of iodine, or loss of the thyroid, or lack of TSH can cause
mucopolysaccharide infiltration of the spaces between cells of the skin and muscle. - Myxedema
-
The tongue
can become thicker, also the hands and face become puffy. Anemia and mental apathy,
sensitivity to cold are also symptoms. - Myxedema
-
Sx:
1. Increased heart rate; increased cardiac output
2. Anorexia (excess catabolism)
3. Poor thermoregulation (excessive heat, sweating)
4. “Toxic†goiter (from inflammation) - Hyperthyroidism
- Autoantibodies against one’s own TSH receptors on acinar cells of the thyroid lead to an overproduction and release of T4 and T3
- Graves’ Disease
- Autoantibodies against Tg or other thyroid cell proteins lead to infiltration of cytotoxic T-cells
- Hashimoto’s Disease
-
plug up the machinery needed for iodine uptake and incorporation to
hormones - Hashimoto’s Disease
- Somet hyroid cancers: are due to exposure to
- radioactive iodine
- treatment for hypothyroidism
- hormone replacement
- treatment for hyperthyroidism
-
hormone ANTAGONIST to block the peroxidase enzyme so that less
hormone is made - prodrug of MMI that is converted to MMI in vivo
- Carbimazole
- Bile acids are primarily synthesized in the liver from
- CHOL
- an intermediate in the synthesis of all the steroid hormones
- Pregnenolone
- stimulates formation of pregnenolone.
- ACTH from Ant. Pitu.
-
two hydroxylation steps (at C20 and C22), followed by cleavage of the side chain in front of C22 by
enzyme = desmolase - Pregnenolone
- primarily made by the corpus luteum and the placenta
- Progesterone
-
Four steps, from progesterone: three additions of -OH (C17, then
C11, C21, = cortisol), then oxidation - glucocorticoids
- PREGNENOLONE from CHOL
- hydroxylate and cleave side chain
- aldosterone, from progesterone:
- 3 oh'ns followed by oxidation
- If reduce the ∆4 double bond of an androgen, you get 5α dihydrotestosterone, a
- more potent androgen
- estradiol, from testosterone:
-
1) clip the C19 methyl
2) reduce the 3=O to 3-OH;
3) aromatize the A ring.
Steps require NADPH + O2 - Steps require NADPH + O2
- formation of estradiol from testosterone