,, ...

- :r
; ·_._,_.·_;
' { -.
Ad re ~ _;ic A.qeds

Adrenergic drugs exe1i their principal pharmacological _and therapeutic

· effects by either enhancing or reducing the activity of the various
components of the sympathetic division of the autonomic nervous system.
In general, substances that produce effects similar to stimulation of
sympathetic nervous activity are known as sympathomimetics or
adrenergic stimulants . Those that decrease sympathetic activity are refened
Lu as symputhulytic:s , antiadrenerglcs, or adrenergic-blocking agents.

Adrenergic agents act on adrenergic receptors (adrenoceptors, ARs) or

affect the life cycle of adrenergic neurotransmitters · (NTs ), including
norepinephtine (NE, noradrenaline), epinephrine (E, adrenaline), and
dopa~ine (DA) . These NTs mo.dulate many vital functions~ such, ?J:S the rate
and force of cardiac contraction, constriction, and dilation of _~lciod vessels
and bronchioles, the release of ins~lin, and the bteakdowrt of fat. Therefore,
adrenergic drugs constitute a broad class of agents, including albuterol (a
bro_n chodilator), atenolol (an antihypertensive), and inart)L:..corhmon over-
the-counter(OTC) drugs . ·
.•. :- ·

Adrenergic Neurotransmitters:
NE, E, and DA are chemically catecholamines (CAs), which refer generally
to all organic compounds th~t contain a catechol hutleus (ortho-
dihydroxybenzene) and an ethylamine group. In a physiological context,
the term usually means DA arid its metabolites NE and B. E contains one
secondary amino group and three hydroxyl groups. _ .

. ~- HO~NH2
HOD ~
1 "2
' .,// l ~ Et~y~amine
HO HO
'-v--'
·-r . .
-catechql

Catechol · P~~~~rgz
··.·'-' c,-;., ·:· ·~. •'· •" .•
 • f ~

Adfe nergic Agents Dr. Noor H A ldabagh j

' ' And related compounds Ph D. Pharmaceutical Chemistry

---------'---- ~/

Ho . cb~r~ ~Q~~,c~,
HO HO

Norepinephrin e (NE) Epinephrine (E)

Like most phenols, the catechol functional groups in CAs are highly
susceptible to facile oxidation . E and NE undergo oxidation in the presence
of oxygen (air) or other oxidizing agents to produce a quinone analog,
which undergoes further reactions to give mixtures of colored products, one
of which is adrenochrome. Hence, solutions of these drugs often are
stabilized by the addition of an antioxidant (reducing agent) such as
ascorbic acid or: sodium bisulfite. E and NE each possess a chiral carbon
. atom; ··.thus; .·each· can exist as •'an · ertantiorheric pair .of isomers. The
.. :· ;
.. ,, '

. enanfromer with the .(R) configuration .is biosynthesized Sy the body and
possesses the biological activity. This (R) configuration of rna_n y other
. adrenergic agents also contributes to their high affinity to the

. :_ . ·· : . : '

OH . OH
. ·=.. . ~

0
{0)
~

:- .. .:··

Epineph ri ne {E ) A quinone analog

Oxidation of Epinephrine (E)

Biosynthesis of Catecholamines:
CAs in . neuroendocri ne cell s are m a state of constant flu x. They are
con tinuous ly being synthesized, relea sed, and metabolized, yet they
maintain a remarkable constant level in tissues. CAs are widel y distributed
in. m~~mal;, ·~d fheir :ievels ·and physiological ·functions are regulated at

martysites. Th~ biosynthesis involves a sequence of enzymatic reactions.

 .Ad ·energic Ag:: 1 s
Ar:d relater co rripou nris
-- - -..-- - -· - -- ---- ---- -

--·LL
iQ
l.J
t\.lhl'-"i:> ·~Lh
.J
u rfr
1 1;
rw vl~tirm
'- ' ' V ' " J
n f thF>
1 \..4 \. 0..._,, , .. . "'-' " ... . , _
::iminl'l
.,.,., •• .._ ,,,,.· ._..
..

acid L-tvrosine to form L-dihvdroxvohenvlalanine (L-DOPA) . L-Tyrosine

• .,/ •• • ..,, .,; .L ., . .... . , ...

is normally present in the circulation and transported actively into the

adrenergic neuron, where it is 3-hydroxylated by tyrosine hydroxylase --
(TH). TH is stereospecific and requires mol ecular 0 2 , Fe+2, and a
tetrahydropteridine cofactor. As usual for the first enzyme in a biosynthetic
pathway, TH hydroxylation is the rate-limi.ting step in the biosynthesis of
NE. Further proof that this step is rate limiting in CA biosynthesis is that
inhibitors of TH markedly reduce endogenous NE and DA in the brain and
NE in the heart, . spleen, and other sympathetically innervated tissues. This
-__ e,nzyme plays -a key role in the regulation of CA biosynthe.sis and is,
- . . . . . .. .

the.logical biological target of some drugs.

therefore,
.> ·: ·, -Sodi~t~r~t:lf~~ti':v~;: jJ'H \.inhibitors include a-:methyl-p-tyrosi~e';a~n1ethyl"'3~
. ~ .

iodotyrosine, ahd a-methyl-5-hydi-oxytryptophan. Most of the agents in this

·',:caJegory · act as·. competitive · inhibitors of TH. a-M~thyl..,p~tyrosirte
(n:ietyfosii1e} and its methyl ester have been the TH inhibitors rriost widely
~ :·:ij,~~- . •.. - - . - - - .

- ·_"
_-._·_--_. ; _,.-_. __.-_-___, ·_--.-__c_.,·:___ :_i-.~l-·._~-~,;_e.'_- ,:~_:_- :_, t.;_.o:_-,• ~_,·_ -c_)i.·:_~':m_::_.:~_·:_. :·ri_·~:,_f_~-a~t-e-. th_e_effe_ ~ts_ o·_f__ e_x_e_rci.qe,_st_r_.es_s-~ ~nd v~rt6ti.~ _o~hk~rsn. !he
.. .. ___ •. .. ___

.--: -~+>ttit~nCii.veif;.._: o:f ':CAs- and to - ··lower NE . forinaffon - in· -'r~a{}g~t.$ . :2·w ith -~
'J"~,:~~~~6~i~~:~;~~:.'and nfaligriant hypertension. · · '"
Tlte secon~step in CA biosynthesis, is the decarboxylation ofL-DOPA to
- give DA, which is ~n imp01iant neurotransmitter and a d.11.ig. Th~ erifyme
involved is DOPA decarboxy lase. Although originally beli eved to remove
carboxyl groups only from L-DOPA, a study of purified enzyme
preparations and specific inhibitors demonstrated that DOPA
decarboxylase acts on all naturally occurring aromatic L-amino acids,
in cluding L-histidine (precursor in th e biosynthesis of histamine), L-
tyro sine, L-tryptophan (precursor in the biosynthesis of 5-HT) , and L-
-·pheriylalaninein add.ition to L~J?.QPA. _
 Adrenergic A gen Dr. Noor H Aldabag h ,. .
And relate d compounais Ph.D. Pharma ceutical Chemis t 1

~
<·:·~,:fhefef6i~e/· trfrs: ~~j~i1~·- i~:::·1_7~9h~·,.,~~pprepr1 M~1y r~ferred 'to,·a3::~r:;~~iromatic ..· ..
amino acid decarboxylase (AADC) . . In addition . to being found in
catecholaminergic n eurons, AADC is found in high concentrations in many

other tissues, includ ing the liver and kidneys.

Parkinsonism can be characterized as a DA deficiency in the brain. Thus,
increas ing brain levels of DA should ameliorate the symptoms.
Unfortunately, direct parenteral DA administration is useless because the
compound does not penetrate the blood-brain barrier (BBB). However, oral
dosing with L-OOP A (levodopa) could act as a prodrug because it entered
the brain (on a specific carrier) and then was decarboxylated to DA there.
LDOP A is effectiv:e and decrease tremor and rigidity. Unfortunately, many
adverse systemic·effects were the result of the high doses needed to achieve
the desired.. results·~ · The . m~!n: xeason is ·the re fati vely .fogher concentration
of AADC in peripheral system than in the brain. Inhibition of peripheral
AADC activity ·by co-administration of at · peripheral decarboxylase
inhibitor such as . carbidopa, can markedly ·increase the proportion of
l~vo~oHa\~hat ·~~~~~~s :the :BBB:'(f3i6od ~rain B~trier). '· i >. , :<
.. .· .: . The "thi~~d ~'tep: ili "cX· hfo'syO,Jh'~s·rs, f.~(side::ch~in)i~ HydrSxyYatl'O'~ of DA
· to give NE .. DA ··roir;;~d · i~- th~ '· cytopla~~ of the ·· neur~fr' i$ •actively

transpo1ied into storage ves icles by the ves icular monoamine ·transporter
(VMA T) and is then hydroxy lated stereospecifically at the ,B-carbon to NE
inside the vesicl e by dopamine ,B-hydroxylase (DBH). The NE formed is
stored in the ~esicles until depolari zati on of the neuron ' initiates the process
of ves icle fusio~ with the plasma membrane and ext~si6n of NE into the
synaptic cleft.

The last step in CA biosynthesis, is the N-methylation of l\'E to gi ve E in

the adrenal
,,
.
medulla.
, ,-
The reaction is catalyzed by the . enzyme
phenyletha~oi~~ine.,N~methyltransforase crNMt). >PNMT is . ~ · cytosolic

enzyme and the methyl d6nor is required for the N-methylation..df NE. The •
.>'
, ·.-; ·:::nergic Age :;ts !;··.JVoor ·-r. · '· 1 ·~ ,.. ;

A red :-ela.t ed corripounc:s , . :.~.1. l"hannacewica.i C1 ,e; . : uy

the storage granules of the chromaffin cells.

Metyroslne (Oe1nser) Carbidopa

(An c1 -methyl anal~ of tyrosine and an Inhibitor of TH)

L~Jyros in e L-Dihydroxyphenylalanirie (L-Dop:a) ·. · Dopamine (DA)

-. ' ·• .''-- ;:;

,. .

.. QH. · OH
:P:~~-rwJe~~~~Pi!~e~::.~ ·~: 1-1
. Do.pamine (;-Hy<J;o;.'. yla~e (DSH} HO /./·rne\h1ltranslerase (PENMT) · N".
CH;
---~ -------:..._"--- ·- ------ -- ~

·'

·~· - ._
'\;· .- ~\-::· ._

;B lMyn-th es is of Caiec liotamifie~ · /dopaniin e, efe.in~phrl~e, 'a~J:~:;;;~pfh,~ph rin e)

Drugs Affecting Catecholamine Bio:synthesis

Metyrosine (a.-Methyl-L-tyrosine, Demser). Although inhibition of any of
the three enzymes involved in CA biosynthesis -- should ·- decrease CAs,
lnhibitors of the first and the rate-limiting enzyrµe TH would be the most
. - . - ·- . .

effective. As such, metyrosine is a much more effective competitive

inhibitor of E and NE production than agents that inhibit any of the other
enzymes irwol ved in CA biosynthesis. Metyrosine differs structurally from
'tyli9sine
.;,,_t : .
only in the presehce
. .
bf'~rt- a~fuethyl grnup.'
.. . .
Ii·•'is .one'
.
example
.
of a ·~
 '- .
Adrenergic Agents Dr.Noor H Aldabagh
And .related comp ounds PhD. Pharmaceutical Chemistry

racemic mixture; it is the (-) isomer that possesses the inhibitory activity.

C0 2 H

HO a-methyl-I-tyrosine

Storage and Release of Catecholamines

A large percentage of the NE present is located within highly specialized
subcellular particles (later shown to be synaptic vesicles but colloquially
referred to as granule.c;) in sympathetic nerve endings and chromaffin eel Is.
Much of the NE in CNS is also located within similar vesicles. Once NE
has exerted its -~ffect at adrenergic receptors, there must be mechanisms for
• ' t. .• . . . • •

rerri6Virig ·'tife1m <f~dm · : the:··syrtapse"~ · and ;terminating its action at the

receptors. These mechanisms include;

• Reuptake of NE' into the presynaptic neuron (recycling, maJor

. ; ·~· m~ch_ an~~m}i.nto extrariel1ron'1-lti~su~s,

.·-·}.--:~_,~ -., ~- ~:~(t-.=-}:(:·:~:.-:- .. ::~~-- ·:.~ ~:· r:..:.,,;;.::,;:;::._=~~:.:· ·· ~.:~. 1 ... ·

•, . ~~Q~v-~i*~?~ o(N.p; to an i~q.:9tiv~ ~et~?clite .

;; · • ·-.: .1 ' . . . • , D.iffosio_B·ofthe NE away frorp. the synapse.
! ; .~ ~-··:·,.-·. . :·:~'-.~ .. - ; _ : : : ; · .... _~_\. ~-·

The first .tw.o of these mechanisms require specific transport proteins or

enzymes, and therefore are targets for pharmacologic intervention.

Meta bolism .of Catecholamines. The second mechani sm of CA rem oval is

metab~,lism. The major mammalian enzymes of importance in the CA
metabolism are monoamme oxidase (MAO) and catechol-0-
methyltransferase (COMT),
Both E and NE are orally inactive and have shon durations of action

·.· p¢c~µse of
,_ . -
th,e~r
-.
.
; high hyd,r_
-··-·
.
oppilict1Y,
.
. ·. ..
ion~zat.
. .
ion '" a.nd extensive first-pass
. . _· .· . ' ... . . .~.

· metabolic d~activation . by COMT and MAO. The first :enzyme of

importance in the metabolism of CAs in the adrenergic neurons of human
 ~

. '
A drene rgic Agents r;,,.__- ·c-~,, H. Ale a agh
' And rela ted ~ompounds PhD. r iwmw ceutical Chemi.s . y
-,----~~~~~~~-~

brail-1 aird !]'~ripfieral tissu~s is i\i.A O. Mj\ Os oxidatively deaxhinate CAs to.
their correspo11ding aldehydes, which are . rapidly oxidized to the
corresponding acid by the enzyme aldehyde dehydrogenase (AD). In some
ci rcumstances , th e al dehyde is reduced to the gl yco l by aldehyd e reductase
(AR) . It is primarily this glycol metabolite that is released into the
'
circu lation, \\Mere it undergoes methylation by the COMT that it
-.....
encounters in non-neuronal tissues. The product of methylation, 3-
.. -
methoxy-4-hydroxyphenylethylene glycol, 1s oxidized by alcohol
- --
dehydrogenase and AD to gi ve 3-methoxy-4-hydroxymandelic acid. This
metabolite comryionly is referred to as vanillylmandelic acid (VMA), and is
the maj"or end product of several pathways of NE metabolism. MAO
·.iriliibito_r's . (MAOis}
- - . . .. .
prevent MAO-catalyzed deami~atiot'.1- .o f NE, DA, and . ."'

·:: ;.::.s,~Ii:tAr8Jii,ci~1j1~l:tli~ir-.. reupfake i~to the nerve .· teimiri~t\%t~0~nt~~;. synaptic

deft. As · a re~ult, higher concentration of the NTs v1{1t· b~· 'ifored in the
\'.:~si:Cl.e~tafi.d become available for release from the presyhifi:pti2:tern1iiiais on
. . ·_...~<:g:~tj}m\d,_ A.rtti~ej:>ressants such as phenelzine are MAO Is. : .

','.' ~:#~}~i~f'~~d~::~hJ~*:i:n;;e:~:tt~t~;~'~j~~~~f:~:a~
·.<by COMT ·occurs almost exclusively on .the · tneta.:.Q.H' ·gtoµp · qf the
catechor, regardless of whether the catechol is NE, E, or one of the
. metabolic products. For example, the action of COMT on NB and E gives
normetanephrine and metanephrine, respectively. A converging pattern of
.,__

-
.........
the metabolism of NE and E in which 3-methoxy-4-hydroxymandelic acid
....... .
(VMA) and 3-inethoxy-4-hydroxyphenylethylene glycol are common end
products thus occurs, regardless of whether the first metabolic step is
ox idation by MAO or 0 -methylation by COMT. These pathways of
met_abo lism are also important to drugs that are structural analogs of NE .
tolcaporie . (tasmar)R and ~ntatap<;me (Co~tant · a,t~ COMT inliib_itors •
pre-s ently available.
 Ad renergic Agents Dr. Noor H. Aldabagh
A nd related comp ounds PhD. Phamiaceutical Chemis try
- - - - - - - - -----i_s_ '
. ,_;, /·

HOx:fOH
I~ CHO

/,/ .
HO

3',4'-Dihydr oxyphenyl-glycolaldehyde Norepinephrine (NE): R H = 3',4'-Dihydroxymandelic Acid

(DOPGAL ) Epinephrine (E) R = CH 3

Aldehyde Reductase
JCOMT
OH J
HOx
I ~: f cH,ofi "''°~""'
HO
/,/ .
N
HO
COMT

3' ,4'-Dihydroxyphenylethylene Glycol Norinetanephrine: R =H

l':~MT· A:~,:::::~~~"
1)MA0
2) Ald~hyde Dehydrogenase
" ."CH,

OH
H)Co: d o H
I ~ . CH20H ·. · 1) Alcohol Dehydrogenase
2)_Aidehyde Dehydrogenase e,oo~~"
;10
/,/ .
HON
. 3'-Methoxy-4' -hydrox'y-phenYlethylene Glycol 3'-Methoxf4'.ctlYdroxy.-rnaJ)delic Ac.id
'/" . :-.·. :· .. -~: _,. . ~-- . . . ' fV.a.nlllyl~~:1:fdffiJt9''1~!~: (VMA)l. · . .
. ( · '?; A maJ&i'en_ a pfo'.dact ·
·.·: -:·;:;:.'",;__ _ .•. .. ,;!:
-~

. Metabolism ofEpin,epifrinf!. a:JJd:,Norepinep.hrine ,by. MAQ. ~nd COM1:

' .
 Adrenergic Agents Dr.No.or l-f.. Aldabagh
And related compounds Ph.D. Pha nna ceutical· Chemistry
~~~~~~~~ -~

Drugs Aff ecting Catech ofo mhe Storage and Release

Reserpine (an NT Depleter).

Reserpine is an indole alkaloid obtained from the root of Rauwolfia
serpentina. It not only depletes the vesicle storage of NE in sympathetic
neurons in PNS, neuro ns of the CNS, and E in the adrenal medulla, but also
depletes the storage of serotonin and DA in theii· respective neurons in the
brain. Reserpine binds extremely tightly with and blocks VMA T that
transports NE and other biogenic amines from the cytoplasm into the
storage vesicles. Thus in sympathetic neurons, NE, which normally is
transported into the storage vesicles, is inste~d. metabolized by
'...· .·

mitochori.d,rial MAO in the cytoplasm. In addition, thereis a gtadual loss of

. -

· ~e~I6l'eb:
..
sfoted·. Nfr-asit
-
is used up hy release resulti~~:;{fatr{:; ~ym:pathetic
"";---, : ~· .' < .. .. ,~:-~\~. ';_;. ;;;· .
·
nerv e activity so that the storage vesicles eventually become 'd)::sfunctional.
' The ~end result. is;;!a depletion of NE in the sympatheti.c: n~~f~·ri: ..Ai.ralogous
effects are seen in the adrenal medulla with E and with .5·11T ( 5-hydroxy
.~- . ;-~_-\ ·. ·/·;y~~t..:··
·.~·· '.·~ .. . .:' . . . .. ; ~_: . -_. -~: ;< --~~-· :·<. . ' . ,. . ~- -, \ . . . ... . . . . :;
J fypt,arhine) in s.eroton.ergi9 -p eutoris. . . ,-

" •.·.
··;
' ' , :;~: ..
.. -~· ._.

-,