450: Medicinal Chemistry Adrenergics

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1
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Norepinephrine

2
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Epinephrine

3
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Dopamine

4

Norepinephrine and Epinephrine act on receptor _____ to increase HR and BP.

Beta1

5

Norepinephrine and Epinephrine act on receptor _____ during peripheral vasoconstriction.

alpha1

6

Epinephrine acts on receptor ____ to increase lipid breakdown.

beta2

7

Epinephrine acts on receptor ____ for coronary and bronchial dilation.

beta2

8

Epinephrine acts on receptor ____ to convert glycogen to glucose.

beta2

9

Enzyme?

Tyrosine --> L-DOPA

tyrosine hydroxylase

10

What is the rate limiting step in biosynthesis of NE and EPI?

tyrosine hydroxylase; converting tyrosine into L-DOPA

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Enzyme?

L-DOPA --> Dopamine

DOPA decarboxylase

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Enzyme?

Dopamine --> Norepinephrine

Dopamine-beta hydroxylase

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Enzyme?

Norepinephrine --> Epinephrine

Phenylethanolamine N-methyltransferase

14

Which enzyme can decarboxylate the aromatic amines? (Trp, Tyr, Pha, His)

dopa decarboxylase

15

What is the name of the transporter than brings tyrosine into the cell?

L-aromatic amino acid transporter

16

Reuptake of NE and DA are done by _____ and _____.

NET, DAT

17

After reuptake, NE can be recycled into ________ ________.

storage vesicles

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After reuptake NE can be metabolized by _________ _________.

mitochondrial MAO

19

Norepinephrine that diffuses away from the cell can be metabolized in extraneuronal sites by _______.

COMT

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MAO will add a _______ (functional group) in place of the amine.

carbonyl

H-C=O

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COMT will add a _____ (functional group) in place of the catechol OH group.

methyl group

22

Synthesis of NE and EPI is stereoselective, and is usually in the ____ conformation.

R-enantiomer

23

The _______ is rarely formed in the synthesis of NE and EPI.

S-enantiomer

24

What functional group makes the molecules of EPI and NE polar?

catechol (dihydroxy)

25

What is the pKa of NE?

~9

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Is NE acidic or basic?

fairly basic

27

Is NE protonated at physiological pH (7.4)?

yes (pKa is 9, so 7.4 is more acidic and will ionize NE)

28

Why do we not give NE orally?

Most of the drug will become ionized in the pH of the stomach and will not be able to cross into the blood.

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Storage of NE:

ATP inside storage vesicles is ______ (acidic/basic).

acidic

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Storage of NE:

Storage of NE is possible inside of the vesicles because?

the acidic environment allows NE to remain in the protonated form and, therefore, can bind to the ATP until it is needed.

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Storage of NE:

What is the ratio of NE to ATP?

4:1

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L-Tyrosine

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Metyrosine

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Metyrosine is used in a hypertensive crisis, pheochromocytoma, and is a competitive inhibitor of _____ _______.

tyrosine hydroxylase

35

How does metyrosine lower BP?

It is a competitive inhibitor of tyrosine hydroxylase (which is the rate limiting step) and will cease production of DA, NE, and EPI. Thus inhibiting the SNS response.

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methyldopa

37

Methyldopa is not the active form, and therefore is a ________.

prodrug

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Methyldopa is an inhibitor of _____ _______.

dopa decarboxylase (enzyme that makes dopamine)

39

The active metabolite of Methyldopa is a(n) ______ agonist.

alpha2

40

Methyldopa looks very similar to ______, and can ente via the associated transporter into the cell.

tyrosine

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Guanethidine

42

Guanethidine is taken up into neurons by ______.

NET

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After guanethidine enters the neuron, _____ and _______ package it into NE vesicles.

VMAT and VMAT2

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How does guanethidine work to decrease BP?

It enters the neuron via NET and is packaged into vesicles via VMAT/VMAT2, where it displaces bound NE from ATP and prevents NE from being released into the synapse.

45

Guanethidine is indicated for _____ and ______.

severe HTN and renal HTN

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Receptors:

peripheral vasoconstriction

alpha1

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Receptors:

autoreceptor, feedback inhibition of NE release

alpha2

48

Receptors:

cardiac acceleration, force

beta1

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Receptors:

smooth muscle dilation; skeletal muscle capillary dilation

beta2

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What is the amino acid in the box? What is it responsible for?

Asp; one of the 3 required binding sites to allow binding to the GPCR.

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What are the amino acids that bind to TM3, and TM5? What are the amino acids responsible for?

TM3 = Asp --> drives binding

TM5 = Two Ser -->drives agonism

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Is Alprenolol an agonist or antagonist?

Antagonist

53

What are phenylethanolamine adrenergic agonists used for?

hypotension, asthma, nasal congestion

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R1 group

selectivity of alpha/beta receptors

55

PEAs:

R1 has less than 2 carbons

mixed alpha/beta agonists (mostly alpha)

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PEAs:

R1 has 2 or 3 carbons

beta-selective agonist

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PEAs:

R1 has more than 3 carbons

beta2-selective agonist

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R2 increases _______ and decreases ________ metabolism.

lipophilicity; MAO

59

R2 is typically ___, ____, or _____.

H, methyl, ethyl

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R3 must have at least 1 ____ group at 3', 4', or 5'

OH

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drug?

COMT metabolism?

BBB effects?

How many Carbons?

isoproterenol;

Yes;

polar --> low BBB;

3 carbons --> beta1 and beta2

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drug?

How many carbons?

COMT?

Half-life? Bioavailability?

metaproterenol;

3 --> beta1 and beta 2;

COMT deception with 3' and 5';

longer and more

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drug?

how many carbons?

R-albuterol?

S-albuterol?

COMT metabolism?

albuterol;

4 --> beta2 selective;

active beta2 agonist;

inactive enantiomer with airway reactivity;

methyl added so less susceptible to metabolism

64

What is the enantiomerically pure R-form of albuterol?

Xopenex

65
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Drug?

more potent or less potent than albuterol?

Pirbuterol (Maxair)

less

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Drug?

R1: how many carbons?

onset?

rescue?

salmeterol (Serevent);

many carbons == beta2 and highly lipophilic;

longer onset;

not for rescue

67

What are the two ways sympathomimetics can work?

1. indirect activity = release of NE into synapse (NE are the direct activators)

2. activation of alpha and beta receptors

68

Ephedrine and pseudoephedrine both have a mix of ______ and are ______ of each other.

enantiomers; diastereomers

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enantiomers of ephedrine

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enantiomers of pseudoephedrine

71

Ephedrine/Pseudoephedrine contain no catechol-like groups and operate with exclusively _________ activity.

indirect (no activation of alpha or beta receptors)

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Phenylephrine

73

What type of agonist is phenylephrine?

alpha-receptor selective

74

If a patient is taking an MAOI and an adrenergic, what will be the effect?

Will increase the drug effect (MAO degrades adrenergics, so if inhibited, the drug will remain longer)

75
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S-amphetamine (Dexedrine, Adderall)

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MDMA (ecstasy)

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1. ?

2. ?

1. pseudoephedrine/ephedrine

2. methamphetamine (more lipophilic)

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lisdexamfetamine (Vyvanse)

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Drug?

MOA?

methylphenidate (Ritalin);

potent inhibitor of NET, DAT

80
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class?

physiological effect?

Imidazoline alpha1-AR agonists;

potent vasoconstrictors

81

Clonidine and guanethidine are examples of alpha2-AR agonists. These drugs act initially as _____ agonists and then once in the brain, act as ______ agonists.

alpha1; alpha2