Catecholamines and their Modifications

Amine Group

The amine group is the terminal nitrogen.
Adding a methyl group generally increases beta selectivity.
Increasing the chain length of the molecule also increases beta selectivity.

Catecholamines

Dopamine is the prototypical catecholamine.
Catecholamines have hydroxyl groups.

Noradrenaline

Noradrenaline has a hydroxyl group added to the beta carbon.
This increases its alpha selectivity.

Adrenaline

Adrenaline is similar to noradrenaline, with an additional hydroxyl group on the beta carbon.
Adrenaline also has a methyl group added to the terminal amine, which increases beta selectivity.

Metaraminol

Metaraminol has an additional hydroxyl group on the beta carbon.
It is no longer classified as a catecholamine because it only has one hydroxyl group on the phenol ring.
It is not metabolised by COMT, which prolongs its duration of action.
It has reduced potency and requires higher doses.
Metaraminol has an additional methyl group on the alpha carbon, preventing metabolism by MAO and further prolonging its duration of action.

Ephedrine

Ephedrine has a hydroxyl group on the beta carbon and a methyl group on the alpha carbon.
It has no hydroxyl groups on the phenol ring, which reduces its potency and increases its elimination half-life.
Ephedrine has a methyl group on the amine, which increases its beta selectivity.

Adrenergic Agent Main Structure

The structure required for activity includes a phenyl ring, ethylene linkage, and an amino terminal.
The structure can also include catechol or an aromatic ring, plus a beta-carbon hydroxyl and an amino terminal.

Structure-Activity Relationship (SAR) of Sympathomimetic Agents

The SAR of sympathomimetic agents was studied by analyzing 3 different substituents: phenyl ring substitution, substitution at carbon in the side chain, and substitution at nitrogen.
Hanging an extra hydroxyl group tends to reduce lipid solubility, decreasing CNS penetration.
Adding any additional group significantly increases alpha and beta receptor agonist.
Additional groups block MAO activity, increasing half-life and action time at the synapse.
Amine group size affects alpha or beta effects.
The aromatic ring, with catechol hydroxyl groups, affects the receptor affinity..
Having two polar hydroxyl groups reduces lipid solubility, limiting brain penetration.
Positions 3 and 5 on the molecule often confer beta-2 selectivity with large amino substituents.

Aromatic Ring Substitution

Substituting the aromatic ring with -OH groups at positions 3 and 4 creates catecholamines (e.g., epinephrine).
This gives high affinity for adrenoceptors, enhancing adrenergic activity.
The presence of -OH groups at positions 3 and 4 in the benzene ring maximizes alpha and beta activity.
If these -OH groups are absent, the overall potency decreases.
Phenylephrine is less potent than adrenaline.

Phenyl Ring Substitution

Three-hydroxy substitution is needed for alpha activity.
Four-hydroxy substitution is needed for beta activity.
Three and four-hydroxy substitutions are needed for both alpha and beta activity.
Replacing catechol with resorcinol increases beta 2 selectivity and decreases COMT metabolism for longer duration of action (e.g., terbutaline).

Catechol Replacement

Replacing meta hydroxyl of catechol increases beta 2 selectivity and decreases COMT metabolism (e.g., salbutamol).
Removing the para hydroxyl group from epinephrine produces selective alpha 1 agonists (e.g., phenylephrine).

Substitution on the Aromatic Ring

Resorcinol rings, unlike catechol rings, are not substrates for COMT.
This results in better absorption and a longer duration of action.
Replacing meta -OH with a hydroxymethyl group creates beta-2 selective agonists.
Catechol moiety is more important for a2 activity than for a1 activity.

Substitution at Carbon in Side Chain

Small alkyl groups (methyl or ethyl) at the alpha carbon decrease metabolism by MAO.
Ethyl groups decrease activity, while hydroxyl groups on the beta carbon are essential for activity.

Substitution at Nitrogen

The amino substituent determines alpha/beta receptor selectivity.
Increasing the alkyl group size on the nitrogen decreases activity at the alpha receptor and increases activity at the beta receptor.
Isoproterenol is an example of this phenomenon.

Additional SAR of Adrenergic Agonists

In non-selective beta agonists, substitution at C3 and C4 reduces sensitivity to light/air, increases metabolism by COMT, and decreases absorption and duration of action markedly.
Additional alkyl group causes a distinct increase in beta activity and a lack of alpha activity, but is resistant to MAO.
Presence of catechol groups increases potency.
B-OH group increases effectiveness, while a-methyl groups increase effectiveness.
Tertiary amine or N-substituted groups often inactivate the compound.

Therapeutic Uses of Sympathomimetic Agents

Uses include treating anaphylactic shock, bronchial asthma, cardiogenic shock, delaying parturition, delaying local anesthetic absorption, hypertension, migraine, CNS stimulation in narcolepsy, nasal decongestion, and premature labor.

Adrenergic Antagonist/Blockers

Clinical uses of adrenergic antagonists include treating hypertension, cardiac failure, controlling urinary output, and prostate hyperplasia.
These drugs block adrenergic receptors and prevent catecholamines from acting.
Binding is often reversible.

Adrenergic Antagonists

Adrenergic antagonists inhibit adrenergic receptors.
Divided into subtypes (alpha and beta).
Subtypes further divided into non-selective, a1 selective, a2 selective, B1 selective, B2 selective, (and non-selective Beta).

Alpha Blockers

Non-selective and irreversible alpha blockers (e.g., phenoxybenzamine).
Reversible alpha blockers (e.g., phentolamine, tolazoline).
Selective alpha 1 blockers (e.g., prazosin, terazosin, doxazosin, alfuzosin).
Selective alpha 2 blockers (e.g., yohimbine).

SAR of Alpha 1 Blockers

Quinazoline-4-amine is required for activity.
The acyl moiety influences duration of action.
Doxazosin has a long acting effect.

Therapeutic Uses of Alpha-Adrenergic Blockers

Alpha-blockers can be used for hypertension, pheochromocytoma, hemodynamic shock, peripheral vascular disease, congestive heart failure, benign prostatic hyperplasia, or pulmonary hypertension.

Classification of Beta Blockers

Divided into first (non-selective), second (beta-1 selective), and third (beta-1 selective) generations.
Include drugs like Propranolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Metoprolol, and others.

SAR of Beta Blockers / Adrenergic Antagonists / Sympatholytics

The -OCH2 group is essential for activity between the aromatic ring and ethanolamine groups.
Hydroxyl-bearing carbon in the aryloxy propanolamine side chain plays a critical role in beta-receptor interactions.

Other SAR Considerations

Alkyl amino groups should be secondary amines for optimal activity.
Isopropyl and t-butyl amino groups (e.g., atenolol) increase nucleophilicity.
The two carbon chains are significant for beta blocker activity.
N,N-disubstitution reduces beta-blocking activity.
Aryl rings and their substitutes determine beta 1 antagonist activity.
Alkenyl groups in the ortho position (e.g., oxprenolol, alprenolol) enhance beta antagonist activity.
Many beta blockers have different aryl groups, including phenyl, naphthalene, and indole, e.g., atenolol, propranolol, and pindolol..

Propranolol as a Lead for Beta-Blockers

Substitutions lower activity.
Structural features are important for H-bonding, ionic bonding, and hydrophobic interactions.

Therapeutic Uses of Beta-Adrenergic Blockers

Beta-blockers are used for hypertension, coronary artery disease, arrhythmias, low-dose treatment of heart failure and hypertrophy, chronic glaucoma, hyperthyroidism (Graves' disease), migraine prophylaxis, esophageal varices, or portal hypertension.