[PHA6115 LEC] CHAPTER 3: ADRENERGICS

Drug that promotes sympathetic/parasympathetic activity

Mimetic Agent

Drug that promotes sympathetic activity

Sympathomimetic/Andromimetic

Drug that promotes parasympathetic activity

Parasympathomimetic/Cholinomimetic

Drug that inhibits sympathetic/parasympathetic activity

Blocking agent

Adrenergic blocking agent

Sympatholytic

Cholinergic blocking agent

Anti-muscarinic

Agents that act on adrenoreceptors (AR) and adrenergic \n neurotransmitter (NT)

Adrenergic agents

Epinephrine, norepinephrine, and dopamine

Neurotransmitters

NTs are stored in synaptic nerve endings and maintained by

Vesicular Monoamine Transporter

Uptake 1

Norepinephrine transporter (NET) and dopamine transporters (DT)

NTs are chemically derived from

Tyrosine

(---------------) adds -OH at 3’ position of tyrosine \n producing L-dihydroxyphenylalanine (L-DOPA)

tyrosine hydroxylase (TH)

tyrosine hydroxylase (TH) adds (---) at 3’ position of tyrosine \n producing L-dihydroxyphenylalanine (L-DOPA)

\-OH

tyrosine hydroxylase (TH) adds -OH at 3’ position of tyrosine \n producing (--------)

L-dihydroxyphenylalanine (L-DOPA)

2\. (---------) of L-DOPA by L-amino acid decarboxylase (AADC)

Decarboxylation

2\. Decarboxylation of (------) by L-amino acid decarboxylase (AADC)

L-DOPA

2\. Decarboxylation of L-DOPA by (-----------------)

L-amino acid decarboxylase (AADC)

3\. (-----------------) adds -OH to the side chain and form NE.

Dopamine-β-hydroxylase

3\. Dopamine-β-hydroxylase (DBH) adds (-----) to the side chain and form NE.

\-OH

3\. Dopamine-β-hydroxylase (DBH) adds -OH to the (-------) and form NE.

side chain

3\. Dopamine-β-hydroxylase (DBH) adds -OH to the side chain and form (----------)

NE

4\. (--------------) adds -CH3 to the amino group and forms Epinephrine.

Phenylethanolamine-N-methyltransferase (PNMT)

4\. Phenylethanolamine-N-methyltransferase (PNMT) adds (------) to the amino group and forms Epinephrine.

\-CH3

4\. Phenylethanolamine-N-methyltransferase (PNMT) adds -CH3 to the (------) and forms Epinephrine.

amino group

4\. Phenylethanolamine-N-methyltransferase (PNMT) adds -CH3 to the amino group and forms (-------).

Epinephrine

The neurotransmitters are chemically described as

Catecholamines

Catecholamines are extensively metabolized by

catechol-O-methyltransferase (COMT)

competes with TH, prevents the formation of L-DOPA

Metyrosine

competes with AADC and prevent L-DOPA metabolism, useful for Parkinsonism to ensure Dopa levels in the brain.

Carbidopa

comes from Rauwolfia serpentina, binds VMAT resulting \n to the metabolism of NE by MAO

Reserpine

binds storage vesicle and makes nerve impulse less responsive to signal triggers

Guanethidine and Guanadrel

𝜶1

* Blood Vessels / Skin
* Mucous membranes
* Uterus

𝜶1A

Prostatic Gland Muscle

𝜶2

CNS

𝜷1 (minor 𝜷2 , 𝜷3 )

Heart

* 𝜶1 -smooth muscle contraction
* 𝜷2 - smooth muscle relaxation

Lungs

𝜷1

Kidney

𝜷3

Adipose tissue

binds to the receptors and activates responses like NE

Direct agonist

stimulate release of NE at presynaptic terminal

Indirect agonist 1

block uptake-1

Indirect agonist 2

inhibit NE metabolism

Indirect agonist 3

both direct and indirect agonist activity

Mixed

(----------------------) \n • β-phenylethylamine, catechol ring, (1R)-OH or (2S)-CH3 is required for maximal effect.

Phenylethylamine Adrenergic Agonist

Phenylethylamine Adrenergic Agonist \n • (--------------), catechol ring, (1R)-OH or (2S)-CH3 is required for maximal effect.

β-phenylethylamine

Phenylethylamine Adrenergic Agonist \n • β-phenylethylamine, (---------), (1R)-OH or (2S)-CH3 is required for maximal effect.

catechol ring

Phenylethylamine Adrenergic Agonist \n • β-phenylethylamine, catechol ring, (------) or (2S)-CH3 is required for maximal effect.

(1R)-OH

Phenylethylamine Adrenergic Agonist \n • β-phenylethylamine, catechol ring, (1R)-OH or (2S)-CH3 is required for maximal effect.

(2S)-CH3

Phenylethylamine Adrenergic Agonist

* A (--------) is needed for receptor binding.

Cationic amine

preferential α-agonist activity, some β1-agonist

H at R1

non-selective (𝛼 or β) activity

CH3 at R1

selective β-agonist

large substituents at R1

selective β1 and β2-agonist

isopropyl at R1

selective β2-agonist

tertbutyl at R1

slower MAO deamination

H at R2

R and S isomerism

CH3 at R2

decrease in 𝛼1 activity

R isomer with CH3 at R2

retains α2 and β-receptors activity

S isomer with CH3 at R2

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

C2H5 at R2

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

H at R3

results to R & S isomerism (R3)

OH

optimal for direct action at receptors (OH at R3)

R isomer

slow CNS penetration of drug agent

β-OH

* decreases direct action (especially at β-receptors;
* renders indirect activity by blocking presynaptic uptake-1 \n Possible CNS stimulation (-H = promotes lipophilicity)

2H at R4 and R5

* Optimal direct action at all adrenoreceptors;
* Renders the structure a target for COMT attack;
* No CNS stimulation (-OH = increases hydrophilicity)

2OH at R4 and R5

* decreases direct action;
* provides β2-selective activity, even with α-preferential \n activity (R1 position)

1OH at R4 or R5

Determines receptor selectivity \n α1; α2 ; α and β; β 1 and β2; β2 .

R1

Protonation is required for receptor binding.

Basic amine

Determines vulnerability to MAO and extent of direct action.

R2

optimal distance between aromatic ring and amine

2-C

Determines extent of direct action and CNS activity.

R3

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

R4 and R5

Pharmacophore of Arylimidazoline Adrenergic Agonist

Phenylethylamine within an imidazoline ring.

1 substitution R1

required for potent α-agonist action

2 substitution R1

facilitate central distribution (increase lipophilicity)

promotes α1-receptor selective activity

substitution at R2

catecholic agents

Norepinephrine and Epinephrine

Metabolism of epinephrine and norepinephrine

COMT and MAO (orally inactive, short DOA)

Use of epinephrine and norepinephrine

life-threatening hypotension, hemorrhagic situations, stimulates \n heart (β1), and dilates bronchi (β 2)

non-selective β-agonist with a catechol ring

Isoproterenol

causes non-selective β-receptor activity in isoproterenol

isopropyl moiety

Metabolism of isoproterenol

COMT, sulfation, and glucuronidation

Use of isoproterenol

↑cardiac output, bronchodilation

dual α- and β- agonist/antagonist

Dobutamine

(S) isomer of Dobutamine

α1 -agonist, β 1-agonist

(R) isomer of Dobutamine

α1 -antagonist, potent β1-agonist

Metabolism of Dobutamine

COMT, sulfation, and glucuronidation

Use of Dobutamine

(+) inotropic effect for CHF (primarily due to β 1-agonist activity)

direct-acting α1-agonist

Phenylephrine

SAR that provides provides α1-selectivity to phenylephrine

m-OH

produces COMT resistance and longer DOA to phenylephrine

absence of p-OH

Metabolism of phenylephrine

MAO, sulfation, and glucuronidation (3’-O-glucuronide)

Uses of phenylephrine

open-angle glaucoma, ↑ effects of spinal anesthesia

direct-acting α1-agonist with an arylimidazoline ring

Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline

causes α-selectivity in Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline

o-lipophilic at Phenyl

causes α1-selectivity in Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline

m-/p- bulky lipophilic at Phenyl

Use of Naphazoline, Tetrahydrozoline, Xylometazoline, and Oxymetazoline

topical nasal/ocular decongestants

naphthalene and imidazoline ring

Naphazoline

Tetrahydrozoline

with bulky lipophilic group

Xylometazoline