450: Medicinal Chemistry Adrenergics
Norepinephrine and Epinephrine act on receptor _____ to increase HR and BP.
Norepinephrine and Epinephrine act on receptor _____ during peripheral vasoconstriction.
Epinephrine acts on receptor ____ to increase lipid breakdown.
Epinephrine acts on receptor ____ for coronary and bronchial dilation.
Epinephrine acts on receptor ____ to convert glycogen to glucose.
Tyrosine --> L-DOPA
What is the rate limiting step in biosynthesis of NE and EPI?
tyrosine hydroxylase; converting tyrosine into L-DOPA
L-DOPA --> Dopamine
Dopamine --> Norepinephrine
Norepinephrine --> Epinephrine
Which enzyme can decarboxylate the aromatic amines? (Trp, Tyr, Pha, His)
What is the name of the transporter than brings tyrosine into the cell?
L-aromatic amino acid transporter
Reuptake of NE and DA are done by _____ and _____.
After reuptake, NE can be recycled into ________ ________.
After reuptake NE can be metabolized by _________ _________.
Norepinephrine that diffuses away from the cell can be metabolized in extraneuronal sites by _______.
MAO will add a _______ (functional group) in place of the amine.
COMT will add a _____ (functional group) in place of the catechol OH group.
Synthesis of NE and EPI is stereoselective, and is usually in the ____ conformation.
The _______ is rarely formed in the synthesis of NE and EPI.
What functional group makes the molecules of EPI and NE polar?
What is the pKa of NE?
Is NE acidic or basic?
Is NE protonated at physiological pH (7.4)?
yes (pKa is 9, so 7.4 is more acidic and will ionize NE)
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.
Storage of NE:
ATP inside storage vesicles is ______ (acidic/basic).
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.
Storage of NE:
What is the ratio of NE to ATP?
Metyrosine is used in a hypertensive crisis, pheochromocytoma, and is a competitive inhibitor of _____ _______.
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.
Methyldopa is not the active form, and therefore is a ________.
Methyldopa is an inhibitor of _____ _______.
dopa decarboxylase (enzyme that makes dopamine)
The active metabolite of Methyldopa is a(n) ______ agonist.
Methyldopa looks very similar to ______, and can ente via the associated transporter into the cell.
Guanethidine is taken up into neurons by ______.
After guanethidine enters the neuron, _____ and _______ package it into NE vesicles.
VMAT and VMAT2
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.
Guanethidine is indicated for _____ and ______.
severe HTN and renal HTN
autoreceptor, feedback inhibition of NE release
cardiac acceleration, force
smooth muscle dilation; skeletal muscle capillary dilation
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.
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
Is Alprenolol an agonist or antagonist?
What are phenylethanolamine adrenergic agonists used for?
hypotension, asthma, nasal congestion
selectivity of alpha/beta receptors
R1 has less than 2 carbons
mixed alpha/beta agonists (mostly alpha)
R1 has 2 or 3 carbons
R1 has more than 3 carbons
R2 increases _______ and decreases ________ metabolism.
R2 is typically ___, ____, or _____.
H, methyl, ethyl
R3 must have at least 1 ____ group at 3', 4', or 5'
How many Carbons?
polar --> low BBB;
3 carbons --> beta1 and beta2
How many carbons?
3 --> beta1 and beta 2;
COMT deception with 3' and 5';
longer and more
how many carbons?
4 --> beta2 selective;
active beta2 agonist;
inactive enantiomer with airway reactivity;
methyl added so less susceptible to metabolism
What is the enantiomerically pure R-form of albuterol?
more potent or less potent than albuterol?
R1: how many carbons?
many carbons == beta2 and highly lipophilic;
not for rescue
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
Ephedrine and pseudoephedrine both have a mix of ______ and are ______ of each other.
enantiomers of ephedrine
enantiomers of pseudoephedrine
Ephedrine/Pseudoephedrine contain no catechol-like groups and operate with exclusively _________ activity.
indirect (no activation of alpha or beta receptors)
What type of agonist is phenylephrine?
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)
S-amphetamine (Dexedrine, Adderall)
2. methamphetamine (more lipophilic)
potent inhibitor of NET, DAT
Imidazoline alpha1-AR agonists;
Clonidine and guanethidine are examples of alpha2-AR agonists. These drugs act initially as _____ agonists and then once in the brain, act as ______ agonists.