Lecture 6 - Muscarinic Agonists and Antagonists

necessary SAR aspects of a muscarinic agonist

Quaternary Ammonium (-N+(CH3)3) Charge is required for binding (A basic nitrogen that is ionized at physiological pH is also adequate for binding (3º amines) —> size of alkyl group needs to be methyl or smaller on ionized nitrogen

SAR aspects of a muscarinic agonist

1. Quaternary Ammonium (-N+(CH3)3) or 3º amine for receptor binding

2. Ester linkage (group that can act as H-bond acceptor is sufficient (carbamates, amides for example)

3. Ethylene bridge (increase or decrease in chain length results in decreased activity)

Alkyl substitutions on the alpha carbon of ethylene bridge result in compounds with…

increased nicotinic receptor selectivity

Alkyl substitutions on the beta carbon of ethylene bridge result in compounds with…

increased muscarinic receptor selectivity and an increase in duration of action (slows ester hydrolysis)

what happens if we add groups bigger than methyl to basic structure of muscarinic agonist

loss of activity

Ings rule of 5 for CHAIN agonists

5 atoms = agonist, 6-8 atoms = partial agonist, 9+ atoms = antagonist (atoms meaning atoms between ionized amine and carbonyl group of ester)

configuration/conformation preferentialness of agonists

ubstituent on the beta carbon creates a chiral center. S>>>>>>R in muscarinic agonism + Extended conformer (trans) is a better muscarinic agonist than the folded conformer (cis)

Ring-containing muscarinic agonists do/don’t follow Ing’s rule

DO NOT!!!!!!!!!

SAR of muscarinic antagonist/anticholinergic

1. Aromatic or aliphatic groups; rings better than chains (Bulk important for antagonism)

2. Tertiary carbon with a branching substituent preferably an H-bond donor or acceptor or both improves affinity (binding) for muscarinic receptor

3. Spacer (chain) could be an ester bridge, ether, hydrocarbon. Separates the bulk from the positively charged amine.

4. Cation at physiological pH is important requirement for binding to the muscarinic receptor. Could be a basic tertiary amine or a quaternary ammonium (always positively charged).

5. arakyl group (not necessary) near ionized amine increases affinity for muscarinic receptors

Tropane-based Anticholinergics of Historic Significance MOA

muscarinic receptor antagonists

Tropane-based Anticholinergics of Historic Significance targets

bronchi, pupil, urinary bladder

metabolism of Umeclidinium

molecule undergoes CYP2D6 mediated oxidative O-dealkylation (deactivation), ortho and para aromatic hydroxylation (deactivation), and Phase II glucuronide conjugation due to no ester

how do acetylcholinesterase inhibitors work

inhibition of AChE will increase the half-life of ACh in the synapse

reversible vs pesudo-irreversible acetylcholinesterase inhibitors

reversibles have exposes esters, pesudo-irreversibles have carbamates instead that aren’t prone to ester hydrolysis and form covalent bond with serine on AChE receptor site

if antagonist has quarternary ammonium, then…

can only work in periphery