[3.1] ADRENERGIC AGONISTS

Direct

- binds to the receptors and activates responses like NE.

Phenylethylamine Adrenergic Agonist
Aromatic substituent (R4 and R5): 2H

= decreases direct action (especially at β-receptors;
= renders indirect activity by blocking presynaptic uptake-1
= Possible CNS stimulation

Phenylephrine
METABOLISM

: via MAO, sulfation, and glucuronidation (3'-O-glucuronide)

Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline

direct-acting α1-agonist with an arylimidazoline ring.

Brimonidine

-has pyrazine ring
-more α2A-selective

Metaproterenol, Terbutaline, and Fenoterol
SAR: . • N-substitution

causes less receptor affinity

FENOTEROL

has 2(4-hydroxyphenyl)-1-methylethyl

Albuterol, Pirbuterol, and Salmeterol
SAR: hydroxymethyl replacement for m-OH

results to β2-selectivity.

Levalbuterol description

is a short-acting β2-agonist

Three (3) mechanisms for Adrenergic Agonists

-Direct
-Indirect
-mixed

Indirect

- non-selectively augments NE's action on the synapses
-do not directly bind to the receptors but will do something to encourage activation of receptors

Indirect activities

• It may stimulate release of NE at presynaptic terminal
• It may block uptake-1.
• It may inhibit NE metabolism.

Mixed

- exhibits both direct and indirect agonist activity

Phenylethylamine Adrenergic Agonist

-β-phenylethylamine, catechol ring, (1R)-OH or (2S)-CH3 is required for maximal effect.
-A cationic amine is needed for receptor binding

Phenylethylamine Adrenergic Agonist
Amine substituent (R1): H

preferential α-agonist activity, some β1-agonist

Phenylethylamine Adrenergic Agonist
Amine substituent (R1): CH3

results to non-selective (a or β) activity

Phenylethylamine Adrenergic Agonist
a-carbon substituent (R2): H

no steric hindrance for receptor binding;
Smaller groups = slower MAO deamination

Phenylethylamine Adrenergic Agonist
a-carbon substituent (R2): CH3

results to R & S isomerism in the structure
R isomer = decrease α1 activity;
S isomer = retains α2 and β-receptors activity

Phenylethylamine Adrenergic Agonist
a-carbon substituent (R2): C2H5

Renders β2-selective activity, even with α-preferential activity at the R1 position.

Phenylethylamine Adrenergic Agonist
β-carbon substituent (R3): H

-decrease direct action (especially β receptors)
-increases CNS penetration (if R1 & R2 is CH3)

Phenylethylamine Adrenergic Agonist
β-carbon substituent (R3): OH

-results to R & S isomerism
-R isomer is optimal for direct action at receptors
-β-OH = slow CNS penetration of drug agent

Phenylethylamine Adrenergic Agonist
Aromatic substituent (R4 and R5): 2-OH (catechol)

- Optimal direct action at all adrenoreceptors;
- Renders the structure a target for COMT attack;
- No CNS stimulation

Phenylethylamine Adrenergic Agonist
Aromatic substituent (R4 and R5): 1-OH (monophenol)

= decreases direct action
= provides β2-selective activity, even with α-preferential activity (R1 position)

Arylimidazoline Adrenergic Agonist
Pharmacophore

Phenylethylamine pharmacophore is maintained within an imidazoline ring.

Arylimidazoline Adrenergic Agonist
meta-/para-R2

Promotes α1-receptor selective activity

Phenylethylamine Adrenergic Agonist
2-C

optimal distance between aromatic ring and amine

Phenylethylamine Adrenergic Agonist
Basic amine

Protonation is required for receptor binding.

Phenylethylamine Adrenergic Agonist
R1

Determines receptor selectivity

Phenylethylamine Adrenergic Agonist
R3

Determines extent of direct action and CNS activity.

Phenylethylamine Adrenergic Agonist
R4 & R5

Determines extent of direct action, selectivity, vulnerability to COMT, and ability to cross BBB

Arylimidazoline Adrenergic Agonist
1-C

essential to provide 2-C distance between aromatic ring and amine.

Arylimidazoline Adrenergic Agonist
(imidazole NH)

Lone-pair electrons conjugated with the double bond.

Arylimidazoline Adrenergic Agonist
(imidazole N with double bond)

Localized electrons available for protonation

Arylimidazoline Adrenergic Agonist
R1'

1 or more lipophilic orthosubstitution is required for α-agonism.

Arylimidazoline Adrenergic Agonist
R2

Lipophilic meta- or para- substitution provides selectivity for α1-receptor

Norepinephrine and Epinephrine

also referred to as "catecholic agents"

Norepinephrine and Epinephrine
Metabolism

via by COMT and MAO (orally inactive, short DOA

Norepinephrine and Epinephrine
Use

-life-threatening hypotension
-hemorrhagic situations
-stimulates heart (β1)
-dilates bronchi (β2)

Isoproterenol

non-selective β-agonist with a catechol ring

Isoproterenol
SAR:

isopropyl moiety causes non-selective β-receptor activity

Isoproterenol
METABOLISM:

via COMT, sulfation, and glucuronidation

Isoproterenol
USE:

↑cardiac output, bronchodilation

Dobutamine

dual α- and β- agonist/antagonist

Dobutamine
SAR: (S) isomer:

α1-agonist, β1-agonist

Dobutamine
SAR: (R) isomer:

α1-antagonist, potent β1-agonist

Dobutamine
METABOLISM:

via COMT, sulfation, and glucuronidation

Dobutamine
• USE:

provides (+) inotropic effect for CHF (primarily due to β1-agonist activity)

Phenylephrine

a direct-acting α1-agonist.

Phenylephrine
SAR: m-OH

-provides α1-selectivity
-increases hydrophilicity resulting to poor bioavailability

Phenylephrine
SAR: absence of p-OH

produces COMT resistance and longer DOA

Phenylephrine
• USE:

open-angle glaucoma, ↑ effects of spinal anesthesia

Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline
SAR: o-lipophilic at Phenyl

causes α-selectivity

Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline
SAR: • m-/p- bulky lipophilic at Phenyl

causes α1-selectivity

Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline
USE:

topical nasal/ocular decongestants

NAPHAZOLINE

Naphthalene + imidazoline ring

TETRAHYDROZOLINE

Naphthalene (na nabawasan ng 2 bouble bonds) + imidazoline ring

XYLOMETAZOLINE

(H3C)3C bulky lipophilic grp + arylimidazoline grp

Clonidine

It is a direct-acting α2-agonist with an arylimidazoline ring.

Clonidine
SAR: NH bridge

causes α2-selectivity

Clonidine
SAR: • Cl groups

causes better α2A-activity

Clonidine
USES

-antihypertensive drug (CNS α2A-interaction)

Brimonidine, Apraclonidine, and Tizanidine

structural analogs (imidazoline) of Clonidine.

Brimonidine, Apraclonidine, and Tizanidine
use

glaucoma (apraclonidine and brimonidine);
multiple sclerosis (tizanidine)

Apraclonidine

can cause dangerous BP elevation

Brimonidine

can cross Blood Brain Barrier

APRACLONIDINE

p-amino analog of clonidine

Guanfacine and Guanabenz

structural analogs (non-imidazoline) of Clonidine

Guanfacine and Guanabenz
SAR

2-atom bridge connecting dichlorophenyl moiety and guanidino group is essential for activity.

Guanfacine and Guanabenz
USE

antihypertensive drug (indirect action by inhibiting release of NE)

GUANFACINE

has -CH2C=O

GUANABENZ

has -CH=N

Methyldopa

α2A-prodrug (α-methylated L-DOPA).

Methyldopa
SAR: α2A-selective agonist activity

— DBH adds -OH stereospecifically at the β-carbon resulting to (1R,2S)-α-methylnorepinephrine

Methyldopa
USE

lower blood pressure

Metaproterenol, Terbutaline, and Fenoterol

short-acting β2-agonist (resorcinol bronchodilators)

Metaproterenol, Terbutaline, and Fenoterol
SAR: Resorcinol ring

provides COMT and MAO resistance — longer DOA.

Metaproterenol, Terbutaline, and Fenoterol
USE

bronchodilators (without cardiac stimulation)

METAPROTERENOL

has -N-CH(CH3)2

TERBUTALINE

has -N-C(CH3)3

Albuterol and Pirbuterol

are short-acting β2-agonist

Salmeterol

is a long-acting β2-agonist (Slow onset)

Albuterol, Pirbuterol, and Salmeterol
SAR: Catechol ring modification

leads to COMT and MAO resistance — longer DOA

Albuterol, Pirbuterol, and Salmeterol
USE

bronchodilators

ALBUTEROL

-hydroxymethyl (m-position)
can be R/S (racemic)

PIRBUTEROL

has a pyridine ring

SALMETEROL

has a very bulky N-phenylbutoxyhexyl causing high lipophilicity — longer DOA

Formoterol description

is a long-acting β2- agonist.

Formoterol and Levalbuterol
use

bronchodilators.

Formoterol:
SAR: Isopropyl-p-methoxyphenyl

increases lipophilicity resulting to fast onset

Formoterol:
SAR: 3'-formylamino

results to longer DOA •

Levalbuterol:
SAR: Pure R-isomer of albuterol,

avoid ADRs of racemic albuterol

FORMOTEROL

has 3'-formylamino and isopropyl-p-methoxyphenyl at the N resulting to fast onset and longer duration of action

LEVALBUTEROL

pure R-isomer of albuterol results into absence (or lesser) ADRs associated to the racemic (R/S) albuterol

Phenylethylamine Adrenergic Agonist
R2

Determines vulnerability to MAO and extent of direct action

Phenylethylamine Adrenergic Agonist
Amine substituent (R1): i-propyl, t-butyl, aralky (bulky groups)

Large substituents results to selective β-agonist
(ipropyl = β1 & β2; t-butyl = β2)

Arylimidazoline Adrenergic Agonist
ortho lipophilic substitution (R1')

1 R1' = required for potent α-agonist action;
2 R1' = will facilitate central distribution (increase lipophilicity)

OXYMETAZOLINE

XYLOMETAZOLINE with another -OH substituent m-position in relation to imidazoline ring

Methyldopa
SAR: Decarboxylated by AADC to

(1R,2S)-α-methyldopamine

Metaproterenol, Terbutaline, and Fenoterol
SAR : The large N-substituent

results to β2-selectivity

TIZANIDINE

thiadiazole analog