Med Chem Lectures 1 And 2

Front 1

DURATION of a hormone’s effect depends on:

Back 1

a) FEEDBACK
b) BIOCHEMICAL MECHANISMS

Front 2

Most amino acid modifications have this action

Back 2

SLOW down DEGREDATIVE Enzymes.

Front 3

Releasing or Inhibiting hormones are secreted from the

Back 3

hypothalamus

Front 4

Type of mods:
a. N-acylation
b. N-formylation
c. Cyclization

Back 4

Change the N-terminus

Front 5

pyro-formation, via loss of a water molecule from the transition
state intermediate; symbol is < or “p”

Back 5

Cyclization

Front 6

symbol is < or “p”

Back 6

cyclization

Front 7

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: “des”AA

Back 7

Change the C-terminus

Front 8

how you form a "des"AA

Back 8

remove a terminal AA

Front 9

by removing a C-terminal Gly, the resulting peptide’s new name
starts with the phrase

Back 9

“des-Gly”

Front 10

Two things you can convert the COOH to when modifying a C-terminus

Back 10

amide, ethylamide

Front 11

Ways you can change the interior portion of a sequence

Back 11

chemically modify, "des", replaced L with D

Front 12

Three AAs of TRH

Back 12

GLU-HIS-PRO

Front 13

<Glu-His-Pro-NH2

Back 13

TRH

Front 14

TRH half life

Back 14

4 minutes

Front 15

Active: at picogram levels. No commercial analogs are available.

Back 15

TRH

Front 16

Diagnostic only, for HYPOTHYROIDISM’s cause (& thus treatment)

Back 16

TRH

Front 17

Therapeutic use for TRH

Back 17

NONE

Front 18

After diagnosis with TRH, if a person has a primary problem, something is wrong with their

Back 18

thyroid

Front 19

After diagnosis with TRH, if a person has a secondary problem, something is wrong with their

Back 19

AP

Front 20

After diagnosis with TRH, if a person has a tertiary problem, something is wrong with their

Back 20

hypothalamus

Front 21

Diagnostic use of TRH is in this manner

Back 21

admin TRH IV wait, 15-30 minutes, take TRH levels

Front 22

PyroGLU … GLY-NH2

Back 22

GnRH

Front 23

a 10 AA peptide

Back 23

GnRH

Front 24

duration of action of GnRH

Back 24

3-5 hours

Front 25

Activity: Release LH & FSH from Anterior Pituitary

Back 25

GnRH

Front 26

More than 3000 analogs tested

Back 26

GnRH

Front 27

What TRH would look like if it were an unmodified Glu-His-Pro at physiological pH

Back 27

Zwitterion at N-terminus and (-) at C-terminus

Front 28

Actual TRH, at physiological pH

Back 28

Pyroglutamate at N-terminus and C-terminus is amidated

Front 29

Vasopressin and Oxytocin are secreted from this lobe of the pituitary

Back 29

posterior

Front 30

MSH is secreted from this lobe of the pituitary

Back 30

intermediate

Front 31

Promote reproduction by enhanced follicle development/ovulation

Back 31

GnRH or analog

Front 32

Interfere with reproduction by RECEPTOR DOWN REGULATION

Back 32

GnRH or analog

Front 33

Diagnose potential cause of infertility (hypothalamic or pituitary)

Back 33

GnRH or analog

Front 34

How GnRH is used to treat endometriosis (by reducing levels of estrogen)

Back 34

reducing levels of estrogen

Front 35

Use of GnRH for palliative treatment of prostate cancer works by

Back 35

reducing secretion of testosterone

Front 36

Use of GnRH is palliative treatment of advanced metastatic breast cancer works by

Back 36

reducing levels of estrogen

Front 37

Used for chemical castration (as may be needed with advanced prostate cancer)

Back 37

GnRH or analog

Front 38

Used to suppress LH surges and increase chances of pregnancy

Back 38

GnRH antagonists

Front 39

aka Lutrepulse

Back 39

Gonadorelin

Front 40

pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

Back 40

Gonadorelin

Front 41

route of Gonadorelin admin

Back 41

IV, (not orally available)

Front 42

AA #6 of Gonadorelin = D-Leu, not L-Gly

Back 42

Leuprolide

Front 43

In Leuprolide, the #6 AA is also modified and the C-terminal GLY is replaced with

Back 43

an N-ethylamide

Front 44

15-50 x as potent as GnRH

Back 44

Leuprolide

Front 45

Continuous dosage: shuts off production of estrogens or androgens.

Back 45

Leuprolide

Front 46

Used with children in cases of premature puberty to stop menstruation or to control testosterone
levels.

Back 46

Leuprolide

Front 47

AA #6 of Gonadorelin = modified D-Ser; C-terminal is also modified.

Back 47

Goserelin

Front 48

It is used to treat prostate and breast cancer, to treat endometriosis, or to help thin the endometrium
prior to a hysterectomy.

Back 48

Goserelin

Front 49

AA #6 of Gonadorelin is D-Ala conjugated to a naphthalene double ring structure.

Back 49

Naferelin

Front 50

Its advantage is that it is administered as a nasal spray.

Back 50

Naferelin

Front 51

Enhance fertilization: by BLOCKING the GnRH RECEPTORS they
prevent the LH surge that the anterior pituitary would otherwise induce.

Back 51

GnRH antagonists

Front 52

prevent ovulation and allow greater maturation of the egg in the ovary.

Back 52

GnRH antagonists

Front 53

Effective after only 5 days of treatment, rather than the 26 days required by leuprolide

Back 53

GnRH antagonists

Front 54

Cetrorelix

Back 54

GnRH antagonist

Front 55

aka CRH, or corticorelin, or Acthrel = ACTH releasing hormone

Back 55

CRF - Corticotropin Releasing Factor

Front 56

made of 41 aa's with a synthetic version also available

Back 56

CRF

Front 57

Smallest active peptide derivative of CRH is

Back 57

38 AA long

Front 58

As with TRH and GnRH, the C-terminal
COOH is “blocked” as an amide.

Back 58

CRF

Front 59

Conversion (CRF) of COOH is “blocked” as an amide back to COOH has this effect on its activity

Back 59

drops significantly

Front 60

CRH binds a receptor in the Anterior Pituitary. Signaling
involves adenylate cyclase, resulting in elevated levels of cAMP, then

Back 60

ACTH release

Front 61

Primary Use: Diagnostic, for cases of pituitary defects that present as Cushing’s
Disease

Back 61

CRF

Front 62

elevated levels of hydrocortisone that result from excess secretion of ACTH

Back 62

Cushing’s Disease

Front 63

Other tissues can also secrete ACTH (called __ secretion) and produce Cushing’s symptoms

Back 63

ectopic

Front 64

44 AA, but only 1- 29 are required for activity (so can be produced synthetically).

Back 64

GRF

Front 65

causes release of human Growth Hormone (hGH) from Anterior Pituitary.

Back 65

GRF

Front 66

Diagnostic for kids with idiopathic (the cause is unknown) Growth Hormone
Deficiency (GHD)

Back 66

GRF

Front 67

for cases of GHD where the pituitary works fine, but hypothalamus is not working properly

Back 67

GRF

Front 68

Since GH promotes protein accumulation, __ is also approved as an “orphan drug” in AIDS to counteract protein (and associated weight) loss.

Back 68

GRF

Front 69

Dopamine and Somatostatin are both

Back 69

inhibitory hypothalamic hormones

Front 70

a catecholamine that can act both as a neurotransmitter and as a hormone

Back 70

Dopamine

Front 71

Dopamine receptors of type __, in which adenylate cyclase enzymes are inhibited

Back 71

D2

Front 72

are those responsible for the inhibitory effect of DA at the pituitary

Back 72

Dopamine D2 receptors

Front 73

Uses for DA in hormone therapy

Back 73

NONE

Front 74

Two reasons DA is not used in hormone therapy

Back 74

1.) peripheral effects of DA in vessels
2.) broken down by MAOs and others

Front 75

bromocriptine

Back 75

dopamine agonist

Front 76

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.

Back 76

bromocriptine

Front 77

Cabergoline

Back 77

dopamine agonist with fewer side effects

Front 78

Dopamine (DA), also known as

Back 78

Prolactin-Release Inhibitory Factor, PRIF

Front 79

Since elevated PRL (DA) can promote metastatic breast cancer, __
therapy used in conjunction with regular chemotherapy can be beneficial.

Back 79

bromocriptine

Front 80

14-AA, cyclized peptide

Back 80

somatostatin

Front 81

inhibits release of Growth hormone from anterior pituitary

Back 81

somatostatin

Front 82

Activity requires that the peptide be cyclized

Back 82

somatostatin

Front 83

Parlodel is aka

Back 83

Bromocriptine

Front 84

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.

Back 84

ethylene bridge (-CH2-CH2-)

Front 85

why replacement of S-S bridge in somatostatin with an ethylene bridge is so effective at increasing half-life

Back 85

reducing agents such as Glutathione (Glu-Cys-Gly) cannot break ethylene bonds

Front 86

somatostatin has several sources, not just

Back 86

the hypothalamus

Front 87

Spinal Cord somatostatin is a

Back 87

neurotransmitter

Front 88

a neurotransmitter, and it induces sedation and hypothermia.

Back 88

brain somatostatin

Front 89

inhibits the secretion of gastrin

Back 89

gut somatostatin

Front 90

inhibits the release of insulin and glucagon

Back 90

pancreas somatostatin

Front 91

reason native somatostatin is not used therapeutically

Back 91

half-life is too short

Front 92

therapeutic uses include diabetes, acromegaly, and cancer of the endocrine system

Back 92

non-radioactive somatostatin analogs

Front 93

reason non-radioactive somatostatin analogs have use for treatment of diabetes

Back 93

inhibition of glucagon secretion by somatostatin is greater than its
inhibition of insulin secretion.

Front 94

increases levels of blood sugar

Back 94

glucagon

Front 95

lowers blood sugar by helping it get inside cells

Back 95

insulin

Front 96

inhibit the release of several
hormones that may be hypersecreted by endocrine tumors

Back 96

somatostatin analogs

Front 97

histamine, serotonin, bradykinin,
prostaglandins, vasoactive intestinal peptide

Back 97

hormones that may be hypersecreted by endocrine tumors

Front 98

use of non-radioactive somatostatin analogs in the treatment of eendocrine cancers is

Back 98

palliative (to reduce diarrhea or e-lyte imbalances)

Front 99

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

Back 99

acromegaly

Front 100

many tumor cell types express
RECEPTORS for

Back 100

somatostatin

Front 101

use of radioactive somatostatin analogs for tumors

Back 101

radioactivity is selectively delivered to kill the cells overexpressing somatostatin receptors

Front 102

modified somatostatin analog which OVERALL most effectively inhibits the secretion of GH, insulin and glucagon

Back 102

[D-Trp8] somatostatin

Front 103

70 times more effective than native
somatostatin

Back 103

octreotide

Front 104

modification of somatostatin with mirror images of aa's and COOH to OH yields

Back 104

octreotide (70x more potent)

Front 105

GH is this type of hormone

Back 105

AP

Front 106

191 AA in length, with a MW of 22,000

Back 106

GH

Front 107

GH is much larger than its active region, so the extra size

Back 107

protects or shields the active region from enzymatic destruction

Front 108

portion of GH which actually binds to the receptor

Back 108

the C-terminal ¼ of the molecule
(somewhere within AA146-AA191)

Front 109

The hormone does not move in the blood as a free molecule; rather, it travels
thru the circulatory system adsorbed onto plasma proteins.

Back 109

GH

Front 110

has a lower rate of inactivation by proteolytic enzymes than does free GH

Back 110

Adsorbed GH

Front 111

instead of traveling freely, these three hormones extend their half-lives by adsorbing onto the surface of plasma proteins

Back 111

ADH, oxytocin, and GH

Front 112

Today's source of GH

Back 112

recombinant DNA technology, probably within e.coli

Front 113

somatropin is aka

Back 113

GH

Front 114

Treatment for Children whose growth is abnormally slow
a. Due to lack of endogenous GH
b. Due to chronic renal failure

Back 114

GH

Front 115

Neutropin and Serostim are aka

Back 115

GH

Front 116

Treatment for adults with GH deficiency (due to pituitary or hypothalamic disease, radiation
therapy for cancer)

Back 116

GH

Front 117

Treatment for girls with Turner’s syndrome (where one of the X-chromosomes is partially or
totally missing) – who are also unusually short

Back 117

GH

Front 118

Treatment for body wasting (cachexia) due to HIV-1 or other disease

Back 118

GH

Front 119

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)

Back 119

GH

Front 120

Although GH can increase skeletal mass and strength, why should athletes beware of use for muscle gain?

Back 120

bizarre growth patterns

Front 121

What could happen to an athlete who tries to use GH to gain rapid muscle mass?

Back 121

acromegaly, esp. is those over 18 yrs.

Front 122

Site of Production is primarily in the liver (but included since they work like GH)

Back 122

somatomedins

Front 123

somatomedins are similar to

Back 123

IGFs (Insulin-like Growth Factors)

Front 124

Quite similar to insulin (they have homologies with both the A-chain and the B-chain of
insulin)

Back 124

somatomedins

Front 125

nature’s own “slow release formulation”

Back 125

transport through blood via adsorption to plasma proteins

Front 126

MW a bit larger than insulin with a half-life of about 20 hours

Back 126

somatomedins

Front 127

Act together with GH to promote cartilage growth, stimulate protein
synthesis, stimulate thymidine incorporation into DNA, and stimulate cell division (mitosis).

Back 127

somatomedins

Front 128

198 AA with a MW of about 23,000. Half-life is about 10 minutes. Neither
end of the peptide is blocked

Back 128

prolactin

Front 129

similar in sequence to human GH (homology), and at sufficiently
high levels, bind to each others’ receptors

Back 129

prolactin

Front 130

The best homology for GH and PRL is

Back 130

only 16%

Front 131

when only the first 50 AA in each GH and PRL sequence are considered

Back 131

then the homology increases by half

Front 132

Replacing only 8 AA from GH into
PRL makes a __ that readily binds the GH receptor.

Back 132

mutant PRL

Front 133

Thus, homology is important, but homology between __ is more important.

Back 133

active site amino acids

Front 134

increase stability (half-life)
facilitate secretion
create recognition sites

Back 134

glycosylation - covalent attachment to sugars to N of Asn thru O of Ser or Thr or HyLys

Front 135

–CH2-C(=O)-NH2 becomes –CH2-C(=O)-NH-sugar chain

Back 135

glycosylation

Front 136

which are less active glycosylated proteins are non-glycosylated ones?

Back 136

glycosylated proteins are only 20-25% as active

Front 137

prolactin and TSH are both

Back 137

glycosylated hormones

Front 138

Proteins that are secreted thru the plasma membrane are often

Back 138

glycosylated

Front 139

Prolactin has a synergistic action with __ to promote mammary
gland proliferation and milk let-down

Back 139

estrogen

Front 140

helps release progesterone from luteal cells, which renders the uterus suitable for imbedding of the ovum
if fertilization occurs

Back 140

Prolactin

Front 141

also binds the lactogenic receptor (the receptor to which prolactin binds)

Back 141

GH

Front 142

if GH binds to the lactogenic receptor instead of prolactin, will it stimulate lactation?

Back 142

no

Front 143

Excessive levels of GH may lead to

Back 143

galactorrhea (xs milk production, even after nursing has stopped)

Front 144

high levels of PRL binding to the GH
receptor causes

Back 144

acromegaly

Front 145

There is a synergistic relationship between prolactin and __ release for preparation of the uterus for implantation

Back 145

progesterone

Front 146

The main characteristic of high levels of PRL is

Back 146

infertility

Front 147

How does xs PRL possibly cause infertility?

Back 147

prolactin receptor desensitization

Front 148

increases testosterone production levels that eventually down-regulate
testosterone receptors

Back 148

Leuprolide

Front 149

have high levels of prolactin and are less able to become pregnant

Back 149

New nursing mothers

Front 150

This could be nature’s way of spacing the responsibilities for child-rearing

Back 150

prolactin receptor desensitization

Front 151

In the case of prolactinemia because of a pituitary tumor, __ may be administered to inhibit prolactin secretion.

Back 151

dopamine agonists bromocriptine or cabergoline