Med Chem Lectures 1 and 2
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- DURATION of a hormone’s effect depends on:
-
a) FEEDBACK
b) BIOCHEMICAL MECHANISMS - Most amino acid modifications have this action
- SLOW down DEGREDATIVE Enzymes.
- Releasing or Inhibiting hormones are secreted from the
- hypothalamus
-
Type of mods:
a. N-acylation
b. N-formylation
c. Cyclization - Change the N-terminus
-
pyro-formation, via loss of a water molecule from the transition
state intermediate; symbol is < or “p†- Cyclization
- symbol is < or “pâ€
- cyclization
-
Type of mods:
a. Convert the COOH to an amide (by adding NH2)
b. Convert the COOH to an ethylamide
c. Remove a terminal AA otherwise recognized by an exopeptidase: “desâ€AA - Change the C-terminus
- how you form a "des"AA
- remove a terminal AA
-
by removing a C-terminal Gly, the resulting peptide’s new name
starts with the phrase - “des-Glyâ€
- Two things you can convert the COOH to when modifying a C-terminus
- amide, ethylamide
- Ways you can change the interior portion of a sequence
- chemically modify, "des", replaced L with D
- Three AAs of TRH
- GLU-HIS-PRO
- <Glu-His-Pro-NH2
- TRH
- TRH half life
- 4 minutes
- Active: at picogram levels. No commercial analogs are available.
- TRH
- Diagnostic only, for HYPOTHYROIDISM’s cause (& thus treatment)
- TRH
- Therapeutic use for TRH
- NONE
- After diagnosis with TRH, if a person has a primary problem, something is wrong with their
- thyroid
- After diagnosis with TRH, if a person has a secondary problem, something is wrong with their
- AP
- After diagnosis with TRH, if a person has a tertiary problem, something is wrong with their
- hypothalamus
- Diagnostic use of TRH is in this manner
- admin TRH IV wait, 15-30 minutes, take TRH levels
- PyroGLU ⬦ GLY-NH2
- GnRH
- a 10 AA peptide
- GnRH
- duration of action of GnRH
- 3-5 hours
- Activity: Release LH & FSH from Anterior Pituitary
- GnRH
- More than 3000 analogs tested
- GnRH
- What TRH would look like if it were an unmodified Glu-His-Pro at physiological pH
- Zwitterion at N-terminus and (-) at C-terminus
- Actual TRH, at physiological pH
- Pyroglutamate at N-terminus and C-terminus is amidated
- Vasopressin and Oxytocin are secreted from this lobe of the pituitary
- posterior
- MSH is secreted from this lobe of the pituitary
- intermediate
- Promote reproduction by enhanced follicle development/ovulation
- GnRH or analog
- Interfere with reproduction by RECEPTOR DOWN REGULATION
- GnRH or analog
- Diagnose potential cause of infertility (hypothalamic or pituitary)
- GnRH or analog
- How GnRH is used to treat endometriosis (by reducing levels of estrogen)
- reducing levels of estrogen
- Use of GnRH for palliative treatment of prostate cancer works by
- reducing secretion of testosterone
- Use of GnRH is palliative treatment of advanced metastatic breast cancer works by
- reducing levels of estrogen
- Used for chemical castration (as may be needed with advanced prostate cancer)
- GnRH or analog
- Used to suppress LH surges and increase chances of pregnancy
- GnRH antagonists
- aka Lutrepulse
- Gonadorelin
- pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
- Gonadorelin
- route of Gonadorelin admin
- IV, (not orally available)
- AA #6 of Gonadorelin = D-Leu, not L-Gly
- Leuprolide
- In Leuprolide, the #6 AA is also modified and the C-terminal GLY is replaced with
- an N-ethylamide
- 15-50 x as potent as GnRH
- Leuprolide
- Continuous dosage: shuts off production of estrogens or androgens.
- Leuprolide
-
Used with children in cases of premature puberty to stop menstruation or to control testosterone
levels. - Leuprolide
- AA #6 of Gonadorelin = modified D-Ser; C-terminal is also modified.
- Goserelin
-
It is used to treat prostate and breast cancer, to treat endometriosis, or to help thin the endometrium
prior to a hysterectomy. - Goserelin
- AA #6 of Gonadorelin is D-Ala conjugated to a naphthalene double ring structure.
- Naferelin
- Its advantage is that it is administered as a nasal spray.
- Naferelin
-
Enhance fertilization: by BLOCKING the GnRH RECEPTORS they
prevent the LH surge that the anterior pituitary would otherwise induce. - GnRH antagonists
- prevent ovulation and allow greater maturation of the egg in the ovary.
- GnRH antagonists
- Effective after only 5 days of treatment, rather than the 26 days required by leuprolide
- GnRH antagonists
- Cetrorelix
- GnRH antagonist
- aka CRH, or corticorelin, or Acthrel = ACTH releasing hormone
- CRF - Corticotropin Releasing Factor
- made of 41 aa's with a synthetic version also available
- CRF
- Smallest active peptide derivative of CRH is
- 38 AA long
-
As with TRH and GnRH, the C-terminal
COOH is “blocked†as an amide. - CRF
- Conversion (CRF) of COOH is “blocked†as an amide back to COOH has this effect on its activity
- drops significantly
-
CRH binds a receptor in the Anterior Pituitary. Signaling
involves adenylate cyclase, resulting in elevated levels of cAMP, then - ACTH release
-
Primary Use: Diagnostic, for cases of pituitary defects that present as Cushing’s
Disease - CRF
- elevated levels of hydrocortisone that result from excess secretion of ACTH
- Cushing’s Disease
- Other tissues can also secrete ACTH (called __ secretion) and produce Cushing’s symptoms
- ectopic
- 44 AA, but only 1- 29 are required for activity (so can be produced synthetically).
- GRF
- causes release of human Growth Hormone (hGH) from Anterior Pituitary.
- GRF
-
Diagnostic for kids with idiopathic (the cause is unknown) Growth Hormone
Deficiency (GHD) - GRF
- for cases of GHD where the pituitary works fine, but hypothalamus is not working properly
- GRF
- Since GH promotes protein accumulation, __ is also approved as an “orphan drug†in AIDS to counteract protein (and associated weight) loss.
- GRF
- Dopamine and Somatostatin are both
- inhibitory hypothalamic hormones
- a catecholamine that can act both as a neurotransmitter and as a hormone
- Dopamine
- Dopamine receptors of type __, in which adenylate cyclase enzymes are inhibited
- D2
- are those responsible for the inhibitory effect of DA at the pituitary
- Dopamine D2 receptors
- Uses for DA in hormone therapy
- NONE
- Two reasons DA is not used in hormone therapy
-
1.) peripheral effects of DA in vessels
2.) broken down by MAOs and others - bromocriptine
- dopamine agonist
-
In women with hyperprolactinemia and a pituitary tumor, treatment with __ led to disappearance of the tumor in
45% and stabilization in another 40% over a period of 8 years followup. - bromocriptine
- Cabergoline
- dopamine agonist with fewer side effects
- Dopamine (DA), also known as
- Prolactin-Release Inhibitory Factor, PRIF
-
Since elevated PRL (DA) can promote metastatic breast cancer, __
therapy used in conjunction with regular chemotherapy can be beneficial. - bromocriptine
- 14-AA, cyclized peptide
- somatostatin
- inhibits release of Growth hormone from anterior pituitary
- somatostatin
- Activity requires that the peptide be cyclized
- somatostatin
- Parlodel is aka
- Bromocriptine
-
If replace S-S bridge in somatostatin with an ___ the resulting
peptide has a half-life of 3 hours, instead of the 2-3 minutes exhibited by the native peptide. - ethylene bridge (-CH2-CH2-)
- why replacement of S-S bridge in somatostatin with an ethylene bridge is so effective at increasing half-life
- reducing agents such as Glutathione (Glu-Cys-Gly) cannot break ethylene bonds
- somatostatin has several sources, not just
- the hypothalamus
- Spinal Cord somatostatin is a
- neurotransmitter
- a neurotransmitter, and it induces sedation and hypothermia.
- brain somatostatin
- inhibits the secretion of gastrin
- gut somatostatin
- inhibits the release of insulin and glucagon
- pancreas somatostatin
- reason native somatostatin is not used therapeutically
- half-life is too short
- therapeutic uses include diabetes, acromegaly, and cancer of the endocrine system
- non-radioactive somatostatin analogs
- reason non-radioactive somatostatin analogs have use for treatment of diabetes
-
inhibition of glucagon secretion by somatostatin is greater than its
inhibition of insulin secretion. - increases levels of blood sugar
- glucagon
- lowers blood sugar by helping it get inside cells
- insulin
-
inhibit the release of several
hormones that may be hypersecreted by endocrine tumors - somatostatin analogs
-
histamine, serotonin, bradykinin,
prostaglandins, vasoactive intestinal peptide - hormones that may be hypersecreted by endocrine tumors
- use of non-radioactive somatostatin analogs in the treatment of eendocrine cancers is
- palliative (to reduce diarrhea or e-lyte imbalances)
-
a condition in which too much growth hormone causes an enlargement of
large bones in the hands and feet and the face, along with an enlargement of the nose and lips - acromegaly
-
many tumor cell types express
RECEPTORS for - somatostatin
- use of radioactive somatostatin analogs for tumors
- radioactivity is selectively delivered to kill the cells overexpressing somatostatin receptors
- modified somatostatin analog which OVERALL most effectively inhibits the secretion of GH, insulin and glucagon
- [D-Trp8] somatostatin
-
70 times more effective than native
somatostatin - octreotide
- modification of somatostatin with mirror images of aa's and COOH to OH yields
- octreotide (70x more potent)
- GH is this type of hormone
- AP
- 191 AA in length, with a MW of 22,000
- GH
- GH is much larger than its active region, so the extra size
- protects or shields the active region from enzymatic destruction
- portion of GH which actually binds to the receptor
-
the C-terminal ¼ of the molecule
(somewhere within AA146-AA191) -
The hormone does not move in the blood as a free molecule; rather, it travels
thru the circulatory system adsorbed onto plasma proteins. - GH
- has a lower rate of inactivation by proteolytic enzymes than does free GH
- Adsorbed GH
- instead of traveling freely, these three hormones extend their half-lives by adsorbing onto the surface of plasma proteins
- ADH, oxytocin, and GH
- Today's source of GH
- recombinant DNA technology, probably within e.coli
- somatropin is aka
- GH
-
Treatment for Children whose growth is abnormally slow
a. Due to lack of endogenous GH
b. Due to chronic renal failure - GH
- Neutropin and Serostim are aka
- GH
-
Treatment for adults with GH deficiency (due to pituitary or hypothalamic disease, radiation
therapy for cancer) - GH
-
Treatment for girls with Turner’s syndrome (where one of the X-chromosomes is partially or
totally missing) – who are also unusually short - GH
- Treatment for body wasting (cachexia) due to HIV-1 or other disease
- GH
-
Treatment for cardiac insufficiency in patients (wall of the ventricle is too thin, or promote growth of useful cardiac tissue in some cases of cardiac hypertrophy
– where excess myocardial mass is nonproductive) - GH
- Although GH can increase skeletal mass and strength, why should athletes beware of use for muscle gain?
- bizarre growth patterns
- What could happen to an athlete who tries to use GH to gain rapid muscle mass?
- acromegaly, esp. is those over 18 yrs.
- Site of Production is primarily in the liver (but included since they work like GH)
- somatomedins
- somatomedins are similar to
- IGFs (Insulin-like Growth Factors)
-
Quite similar to insulin (they have homologies with both the A-chain and the B-chain of
insulin) - somatomedins
- nature’s own “slow release formulationâ€
- transport through blood via adsorption to plasma proteins
- MW a bit larger than insulin with a half-life of about 20 hours
- somatomedins
-
Act together with GH to promote cartilage growth, stimulate protein
synthesis, stimulate thymidine incorporation into DNA, and stimulate cell division (mitosis). - somatomedins
-
198 AA with a MW of about 23,000. Half-life is about 10 minutes. Neither
end of the peptide is blocked - prolactin
-
similar in sequence to human GH (homology), and at sufficiently
high levels, bind to each others’ receptors - prolactin
- The best homology for GH and PRL is
- only 16%
- when only the first 50 AA in each GH and PRL sequence are considered
- then the homology increases by half
-
Replacing only 8 AA from GH into
PRL makes a __ that readily binds the GH receptor. - mutant PRL
- Thus, homology is important, but homology between __ is more important.
- active site amino acids
-
increase stability (half-life)
facilitate secretion
create recognition sites - glycosylation - covalent attachment to sugars to N of Asn thru O of Ser or Thr or HyLys
- –CH2-C(=O)-NH2 becomes –CH2-C(=O)-NH-sugar chain
- glycosylation
- which are less active glycosylated proteins are non-glycosylated ones?
- glycosylated proteins are only 20-25% as active
- prolactin and TSH are both
- glycosylated hormones
- Proteins that are secreted thru the plasma membrane are often
- glycosylated
-
Prolactin has a synergistic action with __ to promote mammary
gland proliferation and milk let-down - estrogen
-
helps release progesterone from luteal cells, which renders the uterus suitable for imbedding of the ovum
if fertilization occurs - Prolactin
- also binds the lactogenic receptor (the receptor to which prolactin binds)
- GH
- if GH binds to the lactogenic receptor instead of prolactin, will it stimulate lactation?
- no
- Excessive levels of GH may lead to
- galactorrhea (xs milk production, even after nursing has stopped)
-
high levels of PRL binding to the GH
receptor causes - acromegaly
- There is a synergistic relationship between prolactin and __ release for preparation of the uterus for implantation
- progesterone
- The main characteristic of high levels of PRL is
- infertility
- How does xs PRL possibly cause infertility?
- prolactin receptor desensitization
-
increases testosterone production levels that eventually down-regulate
testosterone receptors - Leuprolide
- have high levels of prolactin and are less able to become pregnant
- New nursing mothers
- This could be nature’s way of spacing the responsibilities for child-rearing
- prolactin receptor desensitization
- In the case of prolactinemia because of a pituitary tumor, __ may be administered to inhibit prolactin secretion.
- dopamine agonists bromocriptine or cabergoline