OUR LADY OF FATIMA U

College of Pharmacy

PHARMACEUTiCAL AND MEDICINAL

AdrenergicAgen
WEEK 16

”f’”XJ. -1 'JL1 LJ™1J *L “›

• At the end of thñ module, the sMdmts are

ex¿iected to:
• Trace the biosynthetic pathways involved in the
action of Adrenergic agents
• Classify and characterize the types of Adrenergic
agents and enumerate drugs under each type
• Identify and interpret structure-activity relationship of
Adrenergic agents
• Apply principles of medicinal chemistry in the
synthesis and characterization of organic medicinal
i. Define Adrenergic agonist and antagonist
Types of Adrenergic agonist and
antagonist
3 SAR of Adrenergic agonist and antagonist

u Read course outcomes

u Read course guide prior to class attendance
u Proactively participate in discussions
u Watch videos related to the topic
u Answer and submit course unit tasks
Please watch the fo3owing video thru the given link.

• Adrenergic agents (MADE EASY)

• NOTE: Tfiis has been assigned to you by your

instructor during the previous meeting.
 I I

II

Biosynthesis of catecholamines

• Found in the urine

Oh
3-Methoxy•4-hydroxy•
rnandclic acid
tVMA)
• Derivatives of beta phenyle&ylamine

• Impt features:
• Location of OH substitutions on the benzene ring
• Nature of substituent on an amino nitrogen
 Sympathomimetie amines
Contain 3.4 **+ ydroxybenzene group
Epinephrine
NE
Isoproterenol
Dopamine
Catechol

• High potency
• OH (3.4) Show highest potency in activating alpha or
beta receptors
• Rapid inactivation
• COMT (POSTSYNAPTICALLY), gut wall
• MAO (intraneurally), liver, gut wall

• Poor penetration into the CNS

• polar
 • having —OH groups at the 3 and 4 positions
• Maximal alpha and beta activity

HO C C NH2

• 3.s dihydroxy
• increase beta 2 activity
• rnetaproterenol
• non cathecolamine
• 3 (hydroxymethy ) 4 Ii•ydroxy)
• increase beta 2 selectivit
• albuterol
• absence of one or both —OH groups on the
phenyl ring
• reduce the potency of the drugs
• increase the bioavailability a0er oral
administration
• Non-catecholamine, prolong the
duration of action
• increase the distribution of the
molecule to the central nervous
system

OH

C CH/NHCHy•HCI
Enhance the beta receptor activity
Tsize of alkyl substituents - Tbeta-receptor activity
Eg. Norepinephrine Hepinephrine

H fiHj

- H0 C — NH

H
Epinephrine

Enhance the beta receptor activity

• Addition of isopropyl at theamino nitrogen
(isoproterenol)

The larger the substituent on the amino group, the

lower the activity at alpha receptors; eg, isoproterenol
 /soproteruaf
Substitution on the Alpha Carbon

@2AO) and prolong Ae action of such drugs,

particularly the noneatecholamines.

• have an enhanced ability to displace

catecholamines from storage sites in
noradrenergic nerves.
Commonly anaehed group = CH3
Alpha-methyl compounds are also called
phenylisopropylamines.

Direct-acting agonists typically have a beta-hyd roxyl

group
this hydroxyl group may be imponant for storage
of sympathomimetic amines in neural vesicles.

TO
 Direct acting agonist

Non - catecholamines
phenylethanolamines
phenylephrine z-arylimidazolines
imetaraminol xylomethazoline
niethoxamine - oxymethazoline
tetrahydrazoline
naphazoline

$-Phenyfsthylamfne

2-arylixnidazolines
xylomethazoline
oxymethazoline
• tetrahydrazoline
naphazoline

—CHP C
»Clonidine
»Methyldopa
»Guanfacine
»guanabenz

chemical name:
2-(2,6-dichlorophenyIamino)-2-imidazoIine

imidazoline derivative
exists as a mesomeric compound.
 ^ i‹*t lii 1 i‹i,s-

• Alpha-methyl DOPA (Aldomet)

• rnetabolically converted to alpha-methyl norepinephrine
• used for treating essential hypertension.

• Nonselective beta agonist

• Isoproterenol

OH
NHCH(CHP)
 Beta z aonists

SALMETEROL xinafoate
 ALBUTEROL

Terbutaline sulfate
 l3‹; r›i: ii lii n:: .-i›ro?t› is!‘›

i. Fenoldopam
• Di receptor agonist
• selectively leads to peripheral vasodilation in
some vascular beds.
» An N drug for the treatment of severe
hypertension

I
OH

9'ir›i: N ti ie* .-u'or› i•!.'›

z. Dopamine
W the immediate metabolic precursor
of norepinephrine
% activates Dr receptors in several vascular beds,
which leads to vasod?ation.
> ephedrine is a noncatechol
phenylisopropylamine

> the first orally active sympathomimetic dmg.

\• activates B receptors - used in asthma.

> it gains access to the CNS - m?d stimulant.

• Indirect sympathomimetic also, promoting

norepinephrin e release
• benzenemethanol n - [i - (methylamino) ethyl] -
sulfate

N HCH 3
I
C C^ 3 • H,SO,
H H 2
Other Sympathomimetics

CH; NH2
V

CHj
Other Sympathomimetics

CMg—C)H ñfl•4§CHg Cl-

Other Sympathomimetics

CH^=
Hh
Other Sympathomimetics

Other Sympathomimetics

NHS
HO

NHS
Tycmnine
Tyramine
> readily metabolized by MAO in the liver
»normally inactive when taken orally because of
a very high first-pass effeY, ie, low
bioavailability.

» Patients taking MAO inhibitors must be very

careful to avoid tyramine-containing foods.
 ADRENOCEPTOR AN'£AGONIST
DRUGS

i. ALPHAADRENERG IC ANTAGONISTS ($
blockers)
a. BETAADRENERGIC ANTAGONISTS (B-
blockers)
• dissociate ñom receptors
an imidazoline derivative p,
non-selective

1.1.2

• related to the nitrogen mustards

' Beta-halolkyalkylamines - forms
irreversible bond by forming an
eleetrophilic compound that will alkylate the
nucleophilic site of the receptor G, -

R’
Azir!dinlum Ion
 . selective alhai -adrenerie blockin

. selective ai -arener oc

NHS
USE/s:
• Antihypertensives
• used for benign prostatic hyperplasia
• side effect: first dose phenomenon

• Yohimbine
• indolealkylarnine alkaloid
• Brand Name: Aphrodvne

• Corynanthine is dphai
selective blocker HtCO,C’
OH
 Aiyloxypropanol
beta 1 seiective are those

Propranolol

essential structures include:

length of side chain
hydroxyl side chain
amine nitrogen +nust be secondary
• (a)-1-(Isopropylamino)-3- Ii•-(=-
methoxyethyl)phenoxy]-z-propanol D(+)-tarlrate.

• Nonseleetive B blockers
• Propaiiolol
• most lipophilic
• Nadolol
• Pindolol
• Peiibiitolol O NHCH(CHj)y
• Carteolol
OH
• Timolol
• Levobiinolol
• Sotalol
Propranolol
• Beta i selective blockers
• para position OH

• cardioselctive

• Acebutolol
• Atenolol
• Betaxolol
• Bisoprolol
• Esiiiolol
• Metoprolol DQ f4HCH(CH,},

• Bblockers with
Ai antagonist N I'
activity Crt«
• Labetalol
• phenylethanolamine
• Carvedilol
• withantioxidant and OCHq
antiproliferative effect
on vascular smooth
ON
muscle
• neuioprotective and
organ protection
 DRUGS AFFECTING NEUROTANSMITTER RELEASE OR UPTAKE

DRUOS AFFECTING NEUROTANSMITTER