Lecture 5 - Nicotinic Agonists and Antagonists

agonist

drug that has high binding affinity and has 100% efficacy

partial agonist

drug that has high binding affinity and has between 0-100% efficacy

inverse agonist

drug that has high binding affinity and has -100% efficacy (opposite of agonist)

antagonist

drug that has high binding affinity and has 0% efficacy (doesn’t create a response when binding to receptor)

nicotinic agonists

drugs that mimic ACh at nicotinic receptors

nicotine at low vs high doses

low dose: nicotine binds to the nicotinic receptor (LGIC) and activates it, opening the channel; nicotine eventually disassociates from receptor and channel closes

high dose: icotine binds to the receptor tightly and does not dissociate readily; ions continue to flow through the LGIC

mechanism of action formula

action + biological target

MOA of nicotine

nicotinic receptor agonist

How does nicotine distribute into the CNS

unionized form of nicotine can cross from periphery into CNS via BBB during absorption, then it can become ionized and bind to a nicotinic receptor

SAR of partial nicotinic agonists

• Protonated secondary amine mimics the N(+) of ACh

• Pyrazine (1,4-diazine) ring N-atoms act as H-bond acceptors and mimic the ester O-atoms of ACh

• Lipophilic, steric bulk increases binding affinity and decreases intrinsic activity (makes it a partial agonist)

• At pH 7.4, it exists predominantly in its ionized form (this form binds to the nicotinic receptor)

• Ionized form is in equilibrium with the un-ionized form (just like nicotine). Un-ionized form crosses the BBB and enters the CNS

partial nicotinic agonists example

Varenicline (Chantix®)

chantix effects

1. Binds to the receptor with high affinity and prevents the ability of nicotine to bind.

2. Blocks the ability of nicotine to activate the mesolimbic dopamine system which is the neuronal mechanism underlying the reward experienced upon smoking.

Organic Cation Transporter

membrane proteins that move positively charged molecules (organic cations) like neurotransmitters (e.g., dopamine), drugs (e.g., metformin), and toxins across cell barriers

nicotinic antagonists

drugs that block ACh at nicotinic receptors

essential SAR component of nicotinic antagonists

bis-quaternary ammonium functional group that binds to the alpha subunits of the nicotinic receptor LGIC

Neuromuscular Antagonists (Neuromuscular Blocking Agents)

type of nicotinic antagonist that bind to the NM subtype of the nicotinic receptor and decrease skeletal muscle contraction

Depolarizing Blocking Agents

type of Neuromuscular Antagonist that bind to the (same site as the ACh binding site, since competitive) LGIC and cause a transient opening of the channel resulting in an influx of ions and depolarization of the post- junctional membrane, followed by a sustained closure of the channel

are Depolarizing Blocking Agents competitive or noncompetitive

competitive

Depolarizing Blocking Agents MOA

neuromuscular junction antagonist

Depolarizing Blocking Agents SAR

1. Bis quaternary ammonium N(+)

2. A 10-atom separation of the two quaternary ammonium nitrogen groups that corresponds to distance between ACh binding sites of receptor

3. Separating group is flexible (chain of single-bonded atoms allowing free rotation)

4. Esters undergo rapid hydrolysis in vivo – result in a short half-life of 5-6 minutes

5. Causes initial depolarization (twitching of skeletal muscles) followed by blockade of contraction

what structural feature indicates “depolarizing”

flexible scaffold/spacer

Non-Depolarizing Agents

type of Neuromuscular Antagonist that bind to the LGIC competitively and DO NOT cause a transient opening of the channel

SAR of Non-Depolarizing Agents

1. Quaternary ammonium N(+) and ionized amine at pH 7.4

2. A 10-atom separation of the quaternary ammonium and ionized amine groups

3. Separating group is bulky and rigid – imparts non-depolarizing activity

4. H-bonding functional groups – mimic acetylcholine

what structural feature indicates “non-depolarizing”

bulky/rigid spacer/scaffolding

Steroid based Neuromuscular Blockers (NMBs) – Non-Depolarizing MOA

nicotinic receptor (Nm) antagonist

Steroid based Neuromuscular Blockers (NMBs) – Non-Depolarizing SAR

1. Bis quaternary ammonium N(+) or ionizable tertiary amine (pH=7.4) + quaternary ammonium

(N+)

2. A 10-atom separation of the two positively charged nitrogen groups

3. Separating group is bulky and rigid steroid skeleton – imparts non-depolarizing activity

4. H-bonding functional groups – mimic acetylcholine’s ester

what patients need to take NMBs with caution

those with liver and/or kidney impairments due to how drug is metabolized and excreted

Which structural feature should cause there to be a decreased rate of ester hydrolysis in steroid-based neuromuscular blockers?

steroid scaffold (shields any esters from hydrolysis)

Benzyltetrahydroisoquinoline-based Neuromuscular Blockers - Non-Depolarizing MOA

nicotinic receptor (Nm) antagonist

Benzyltetrahydroisoquinoline-based Neuromuscular Blockers - Non-Depolarizing SAR

1. Bis quaternary ammonium N(+) at pH 7.4

2. A 10-atom separation of the two quaternary ammonium nitrogen groups

3. Quaternary ammonium nitrogen are embedded in the bulky benzyl tetrahydroisoquinoline ring

system – imparts non-depolarizing activity

4. H-bond acceptor

advantage of Benzyltetrahydroisoquinoline-based Neuromuscular Blockers over NMBs

don’t require hepatic enzymes or renal clearance to be cleared

what does ester hydroylsis do to a drug

deactivates, degrades, or terminate it