Glossary of med chem adrenergic neurotransmission

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NE is the neurotransmittor of the?
postganglionic sympanthetic neurons
interacts with pre & postsynaptic adrenergic receptors
NE & Epi are released from?
from adrenal medulla as neurohormones
also some from in neurons of CNS
what is the basic structure of a catechol?
benzene with 2 OH groups that are ortho to each other
class of NE and Epi
state of NE & Epi at physiologic pH
cations (+NH3)
what is the difference between NE and Epi?
nor - w/o methyl on N
which enantiomer of the catecholamines has biological activity?
R enantiomer
a catechol will be oxidized into what?
how do you stabilize catecholamine drugs?
adding antioxidants such as ascorbic acid or sodium metabisulfite
NE and Epi are synthesized from what aa?
give the order of steps in the synthesis of epi from the beginning
l-tyrosine -> L-DOPA -> dopamine -> NE -> Epi
what inhibits tyrosine hydroxylase
incr concen of epi, NE, DA
which form of tyrosinehydroxylase is active?
the phosphorylated form
what is the methyl donor is the synthesis of epi from NE?
s-adenosyl methionine
when NE is released into the synaptic cleft, what 4 events can occur?
it will stimulate effector cell
it can be taken up by adregergic neuron (stored or metabolized)
it can stimulate alpha2 receptors
it can diffusion into the general circulation
how much of NE is taken back into the adreergic neuron by the uptake-1 system?
the uptake-1 system can be inhibited by? what is the result of this?
tricyclic antidepressants
more NE is left in the synaptic cleft - repeatedly stimulate adrenergic receptors
what is the final molecule that results from the biotransformation of NE & Epi
3-methoxy-4-hydroxymandelic acid aka vanillyl mandelic acid
what is pheochromocytoma?
cancer of the adrenal medulla (more NE & Epi is produced, incr VMA)
what is vanillyl mandelic acid a biomarker for?
catecholamine turnover (incr VMA, incr turnover)
both MAO and COMT occur in all tissues (ubiquitous), but what is the cellular location of each?
MAO - outer membrane of mitochondria
COMT - cytoplasm
however, only MAO is present in neurons!
what are the steps in the extraneuronal biotransformation of NE/Epi?
↝ 1. MAO 2. aldehyde dehydrogenase
3,4-dihydroxymandelic acid
3-methoxy-4-hydroxymandelic acid
what are the steps that occur in the adrenergic neuron in the biotransformation of NE & Epi
NE, Epi
aldehyde reductase
3,4-dihydroxyphenylethylene glycol
3-methoxy-4-hydroxyphenylethylene gylcol
alcohol dehydrogenase
aldehyde dehydrogenase
3-methoxy-4-hydroxymandelic acid
what are the 2 subtypes of adrenergic receptors
alpha & beta
what is the general structure of a adrenergic receptor?
7 transmembrane helical structure coupled to G-proteins
what does the G-protein Gi do?
inhibition of adenylyl cyclase
what does the G-protein Gq do?
stimulation of PLC
what does the G-protein Gs do?
activation of adenylyl cyclase
alpha-1 adrenergic receptors are coupled to
Gq proteins
alpha-2 adrenergic receptors coupled to
beta adrenergic receptors coupled to
which receptors are post-synaptic receptors?
what do the post-synaptic receptors do?
mdiate organ/tissue responses of NE & Epi
which receptor is pre-synaptic?
what do the pre-synaptic receptors do?
modulate the quantity of NE in the synaptic cleft
give the aa that aid in binding NE to the receptor
Ser 204
Ser 267
Phe 290
Asp 113
how does Serine aid in the binding of NE to the receptor?
provides hydrogen bonding with 2 OH groups (transmemembrane domain 5)
how does Phenylalanine aid in the binding of NE to the receptor?
hydrophobic interaction with phenyl ring
how does Aspartate aid in the binding of NE to the receptor?
ionic interaction (TMD 3)
what is isoproterenol?
a catechol that is not endogenous
with regards to size, describe the alpha and beta adrenoceptors
alpha - small space at receptor
beta - larger space, can accommodate bulky sidechains
rank the binding affinity of the catechols to alpha adrenoceptors
NE > Epi > Isoproterenol
rank the binding affinity of the catechols to beta adrenoceptors
isoproterenol > Epi > NE
what is the difference bewteen beta-1 and beta-2 binding of Epi & NE
beta-1 binds Epi & NE with the same affinity
beta-2 binds Epi more strongly than it does NE
adrenoceptor subtype in the heart
adrenoceptor subtype in the lungs
adrenoceptor subtype in the arterioles & vascular smooth muscle
beta-2 (& alpha)
adrenoceptor subtype in the eyes
adrenoceptor subtype in the liver
adrenoceptor subtype in the intestine
adrenoceptor subtype in the kidney
adrenoceptor subtype in the uterus
response of the heart to adrenoceptor stimulation
incr conduction velocity, force & rate of contraction (incr cardiac output)
response of the lungs to adrenoceptor stimulation
relax in tracheal & bronchial smooth muscles (bronchodilation)
response of the arterioles & vascular smooth muscle to adrenoceptor stimulation (alpha-1)
constriction of most peripheral vasculature (cerebral, cutaneous, mucous membrane, visceral)
response of the arterioles & vascular smooth muscle to adrenoceptor stimulation (beta-2)
dilation of skeletal muscle vasculature
response of the eyes to adrenoceptor stimulation
constriction of radial muscle (pupil dilation)
response of the liver to adrenoceptor stimulation
incr gluconeogenesis & glycogenolysis
response of the intestine to adrenoceptor stimulation
decr motility
response of the kidney to adrenoceptor stimulation
incr renin production
response of the uterus to adrenoceptor stimulation (alpha-1)
response of the uterus to adrenoceptor stimulation (beta-2)
adrenoceptor subtype located in the adipocytes
adrenoceptor subtype located in the CNS
response of the adipocytes to adrenoceptor stimulation
incr lipolysis
response of the CNS to adrenoceptor stimulation
reduced sympathetic outflow
drugs that affect the biosynthesis of Epi & NE
drugs that affect the storage of Epi and NE
durgs that affect the release of Epi and NE
what is the brand name for metyrosine?
what is the brane name for reerpine?
brane name for guanethidine
brand name for guanadrel
what is the MOA of metyrosine?
it inhibits tyrosine hydroxylase, decr the biosynthesis of Epi and NE
uses for metyrosine
to manage pre-operative pheochromocytoma
reserpine is isolated from what indian shrub?
raulwofia serpentina
MOA of reserpine
inhibits transport of NE from cytoplasm into storage vehicles
what is the onset of action of reserpine?
works by depleting NE stores - takes time to diminish NE pool - slow onset
what is the duration of action of reserpine?
long lasting because there is no new NE being stored in the vesicles
reserpine is used to treat
severe hypertension
MOA of guanethidine & guanadrel
enter the neuron by uptake-1 process where they stabilizw the storage vesicle membrane to inhibit release of NE
half life and bioavailability of guanethidine & guanadrel
half life: 5 days
bioav: 5%
half life: 12 hours
bioav: 85%

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