Lecture 9 - Drugs that Effect Adrenergic Neurotransmission

Drugs that Inhibit the Biosynthesis of NE

metyrosine

metyrosine MOA

binds to the enzyme, but the extra methyl group in its structure prevent the enzyme from exerting catalytic activity. This results in reversible inhibition of the entire catecholamine cascade

LAAAD inhibitor example

methyldopa

methyldopa MOA

enters the CNS where the enzyme L-AAAD treats methyldopa as a substrate and converts it to alpha-methylnorepinephrine, a false neurotransmitter (alternate substrate)

alternate substrate

compounds that structurally resemble the natural substrate of an enzyme but don’t have natural activity

what happens if methyldopa present in DOPA —> dopamine

decreased rate of conversion (LAAAD enzyme too busy processing methyldopa to care about L-DOPA)

alpha 1 primary location

postsynaptic

what do alpha 1 receptors mediate

responses that lead to smooth muscle contraction (vasoconstriction, uterine contraction, prostate).

alpha 2 primary location

presynaptic in CNS, postsynaptic in periphery

what do alpha 2 receptors mediate

• Regulates release and biosynthesis of NE

• Increases uptake of NE into the presynaptic neuron.

How does neurotransmission differ if it is primary post-synaptic vs pre-synaptic for NE?

presynaptic response is to decrease NE neurotransmission, postsynaptic is to increase NE transmission

classes of direct alpha 1 agonists

phenethanolamines and the 2-aryl imidazolines

Phenethanolamine structural modifications achieve…

alpha agonist activity

Phenethanolamines (derivatives)

phenylephrine and metarminol

Phenethanolamines SAR

1. Amino substituent Needs to be a small group such as an H or a CH3. (Any larger group destroys receptor selectivity.) If an aralkyl substituent such as (CH2)n-Ar (Ar = phenyl) is present, then affinity for the alpha-1 receptor returns with an accompanying loss of intrinsic activity.

2. Substitution on the alpha-carbon can Only small substituents (Me, Et) are tolerated. A methyl group imparts alpha-1 selectivity, while an ethyl group diminishes it. Presence of such substituents on the alpha carbon slows MAO catalyzed metabolism.

3. beta-OH group with the R- configuration imparts maximal direct agonist activity at both the

alpha and beta receptors by enhancing receptor BINDING. An OH group in the S-configuration or total absence results in lower activity due to weaker binding. OH group plays a role in agonist action, but does NOT play a role in alpha/beta receptor selectivity

4. Aromatic (phenyl) ring substituents: Catechol is best, but its chemical/metabolic instability (COMT) results in poor bioavailability. Just a meta OH group results in alpha selectivity and resistance to COMT (e.g., phenylephrine and metaraminol). Absence of all OH groups results in compounds with mixed/indirect acting agonists (e.g., ephedrine, pseudoephedrine, and amphetamine)

2-Aryl Imidazolines SAR

1. Imidazoline ring (five membered ring with two nitrogen atoms and one double bond)

2. Required: 2-position of imidazoline attached to a -CH2 connector group

3. CH2 group connects the imidazoline ring to an aromatic ring

4. Required: Aromatic ring substituents (R1 and R2) are lipophilic alkyl groups (Positioned on the ortho position – prevents free rotation of the aromatic ring and ensures that the imidazoline ring and the aromatic ring are nonplanar; Nonplanarity of the two rings is responsible for selective α1 receptor agonist activity.)

5. Bulk in para position on aromatic ring increase hydrophobicity and alpha 1 selectivity

what is required in 2-aryl imidazoline-based compounds

2-position of imidazoline attached to a -CH2 connector group AND Aromatic ring substituents (R1 and R2) are lipophilic alkyl groups

Indirect acting α1-agonists list

Phenethylamine derivatives

how do Phenethylamine derivatives work

promotes release of norepinephrine from the synaptic vesicles, therefore increasing [NE] in the synapse

Mixed acting alpha-1-agonists (direct and indirect acting) list

Phenethylamine/Phenethanolamine derivatives (with 1 OH group)

Mixed acting alpha-1-agonists (direct and indirect acting) SAR

1. beta OH group increases direct alpha-1 activity (agonist)

2. no H bonding group can cause indirect action

Direct-acting alpha 2-agonist groups

2-amino imidazolines and imidazoline absents

2-amino imidazolines SAR

A. Imidazoline ring (five membered ring with two nitrogen atoms and one double bond)

B. Required: 2-position of imidazoline attached to an –NH connector group

C. NH group connects the imidazoline ring to an aromatic ring

D. Required: Aromatic ring substituents (R1 and R2) are halogens (Cl, Br) Located on the ortho position (must have at least one substituent) that prevents free rotation of the aromatic ring and ensures that the imidazoline ring and the aromatic ring are nonplanar. (Nonplanarity of the two rings is responsible for selective α2 receptor agonist activity.)

issue with clonidine and PNS

clonidine can have alpha-2 agonist properties in periphery, which can increase BP

what form of drugs bind to receptor

ionized versions

imidazoline-absents

guanabenz and guanfacine (imidazoline not required for activity, but needs 1 chloro group in ortho)