Adrenergic Agonists SAR
Adrenergic Agonists SAR
Agonists can select for a1, a2, B1, B2, or non selectively bind to both B receptors.
Or, drugs can act indirectly: drug enters storage granule and displaces Norepi and some dopamine. Most activity is seen at the B receptors.
Mixed agonists select for a1 receptors but demonstrate some results typical of B agonists because they also act indirectly
a- receptor agonist selectivity:
a-1 receptor:
- Phenylethylamine structure must be a primary amine.
- Requires an OH on the B-carbon and an OH at the meta position on the ring
a-2 receptor:
guanidine stucture
B-receptor agonist selectivity:
nonselective B-agonists:
- Phenyethylamine structure must be a secondary amine substituted with an isopropyl (or larger) group
- Catechol ring
B-2 receptor:
- one or both of these structural modifications:
- t-butyl in place of isopropyl
- phenol or resorcinol instead of catechol
B-1 receptor:
- no specific SAR
Indirect adrenergic agonists:
Phenylethylamines lacking both meta and B-carbon Oh groups (if they had those two groups, would select for a-1 instead of acting indirectly)
Adrenergic Antagonist SAR
Antagonists can select for a-1, B-1, or non-selectively bind to and block both B receptors. There are no selective B-2 antagonists. One compound, phenoxybenzamine, selects for both a-receptors. Two compounds, carvedilol and labetalol, block a-1, B-1, and B-2 receptors.
a-receptor agonist selectivity:
a-1 receptor:
- piperazinyl quinazolines
non-selective a-antagonist:
- requires a B-haloalkylamine necessary for an intramolecular reaction required for binding to a-receptors.
B-receptor agonist selectivity:
Antagonists look just like agonists, with a few changes: the aryl group is usually changed (bulkier) and an O-CH2 is added between the aryl and the B-carbon.
Non-selective B-antagonist:
- Aryl group is a two-ring structure
- contains O-CH2 between aryl group and B-carbon
- NO aromatic alcohols
B-1 receptor:
- aryl group is a single benzene ring with a para-substitution of a heteroatom (O,N, or S) containing, non-ionizable group
- O-CH2 present between aryl group and B-carbon
Blood brain barrier
As a general rule, compounds with any OH on benzene rings will not cross blood brain barrier due to ionization.
Metabolism
Adrenergic agonists and antagonists tend to be metabolized by COMT and MAO, which shortens their half –life. Requirements for metabolism by these enzymes:
COMT (catechol O-methyl transferase):
Depends on para and meta hydropxylation of the benzene ring.
Normal metabolism (shortest DOA): catechol form – OH on meta and para
Slow metabolism: OH on meta but not on para
No metabolism by COMT: absence of a meta-OH
MAO (monoamine oxidase):
Compound must have a primary amine or a secondary amine with a methyl group for MAO to be able to metabolize it at all; large groups create steric hindrance. If the drug meets this criteria, it will undergo oxidative deamination by MAO depending on the substitution at the a-carbon:
Normal metabolism (shortest DOA): a-carbon is unsubstituted
Slow metabolism: methyl on a-carbon
No metabolism by MAO: a- carbon has two methyls, or any substitution larger than a methyl.
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