Medicinal Chemistry of Pain Agents

Current agents used for treating pain

• Opioids

• Acetaminophen

• Anti-inflammatories

• Agents used for neuropathic pain

• Agents used to prevent and/or treat headache & migraine

• Topical agents

• Topical analgesics & anesthetics

Opium Alkaloids

• Source: opium poppy (Papaver somniferum)

• PC/MOA: agonism at mu opioid receptors in CNS produces analgesia

• Selected compounds: Morphine (MS Contin), Codeine (Tylenol #3®)

How do opioids act?

Mimic endogenous enkephalins and endorphins

What receptor subtypes do opioids bind to?

- μ

- κ

- δ

What are the risks of opioids?

- tolerance

- dependence

- abuse

- addiction

- overdose

Numbering scheme of opioids

The 2 structural classes of compounds in opioids

- phenanthrenes

- flexible

SAR or opioid agonists: What is the structure of the compound is required for opioid receptor binding*******

Basic (3°) nitrogen required for opioid receptor binding

SAR or opioid agonists: Increasing __________ on the ____ atom flips activity from µ __________ to µ _______________*******

Increasing steric bulk on the N atom flips activity from µ agonist to µ antagonist

SAR or opioid agonists: All phenanthrene-based agents have a __________ or ___________ at C3*******

All phenanthrene-based agents have a phenolic hydroxyl or methoxy ether at C3

SAR or opioid agonists: Converting from a __________ to a ___________ at C6 increases potency*******

Converting from a hydroxyl to a ketone at C6 increases potency

Opioid: conversion from one group to others by eliminating groups

1. nalbuphine-we dont need furan

2. butorphanol- dont need ring

3. meperidine- dont need other ring

Distribution of opioids

Well-distributed throughout the body, including breast milk

Role of pharmacogenetics in the metabolism of opioids*******

CYP2D6

Toxicity issues associated with opioids*******

• Hypersensitivity

• Opioid-induced constipation (OIC)

• Sedation

• Physical & psychological dependence (opioids) & abuse potential (opioids, dextromethorphan)

Morphine (MS Contin)

TC:

PC/MOA:

CC:

TC: analgesic agent

PC/MOA: mu opioid receptor agonist

CC: phenanthrene

Acetaminophen was first marketed as...

- phenacetin in 1955

- withdrawn by FDA in 1983 due to its carcinogenic and kidney-damaging properties

SAR of acetaminophen: Aminophenols, including acetaminophen, are less toxic than the corresponding ___________________ derivatives

aniline (non-OH) derivatives

MOA of acetaminophen

- not fully understood

- may involve activity at TRPV1 receptors or inhibition of the reuptake of endogenous cannabinoids in the CNS

Indications of acetaminophen

Relief of fever and/or pain, particularly in individuals who are sensitive to salicylates

T/F: Antipyretic effects of acetaminophen require CNS/BBB penetration

TRUE

ADMET of acetaminophen

A: oral BA is 88 ± 15%

D: well-distributed throughout body, <20% plasma protein bound

E: via metabolites in urine

T: contraindications: hepatic disease, DDI: alcohol, warfarin

Metabolism of acetaminophen*****

- Major pathways: O-Glucuronidation/sulfation

- Minor toxic pathway: CYP1A2, CYP2E1, CYP3A4-mediated catalysis

- N-Acetyl-para-benzoquinone imine (NAPQI): the reactive benzoquinonemetabolite responsible for acetaminophen's hepatotoxicity

Acetaminophen

- TC:

- PC/MOA:

- CC:

- TC: analgesic & antipyretic

- PC/MOA: unclear, may involve actions at TRPV1 vanilloid & cannabinoid receptors

- CC: substituted phenol

What path of the arachidonic acid cascade do corticosteroids indirectly affect?

Corticosteroids indirectly inhibit phospholipases A2 & C, so arachidonic acid is not released, blocking both COX and LOX pathways. This is why they are anti-inflammatory

Corticosteroid special structures on carbons*******

- Carbonyl group at C3 enhances glucocorticoid activity

- Double bond between C4 and C5 increases glucocorticoid activity

- Halogen substitution (F>Cl>>H) at C9 increases both glucocorticoid activity (better GR ligand) and anti-inflammatory activity (better absorption)

- Oxygen substitution on C11 enhances glucocorticoid activity

- Beta-ketol at C17 increases GC activity & increases topical/inhaled absorption

Glucocorticoid steroids

- TC:

- PC/MOA:

- CC:

- TC: anti-inflammatories

- PC/MOA: GR agonists

- CC: steroids

Relatively non-selective NSAID chemical classes (4)

• Salicylates

• Fenamates (fenamic acids)

• Acetic acids

• Propionic acid

NSAIDs more selective for COX2...

- Oxicams (enolic acids)

COX2 selective NSAIDs

- coxibs

- pyrazolones

What are the risks of NSAIDs*******

- may cause an increased risk of serious CV thrombotic events, MI, stroke

- risk may increase with duration of use

- pts with CV disease or risk factors for CV disease may be at greater risk

What does the FDA require the drug label for all NSAIDs to describe?*******

- risk of kidney problems in unborn babies that result in low amniotic fluid

- recommended to avoid NSAIDs in pregnant women at 20 weeks or later in pregnancy

SAR trends for COX1/nonselective inhibition

- acidic group (typically COOH) required for activity

- aromatic/heteroaromatic ring next to acidic group

- A separate, additional lipophilic group increases affinity for COX enzymes

Most selective COX2 inhibitors (Coxibs) follow a different...

("3-ring") pattern

What agents are more COX1 selective?

- naproxen

- ibuprofen

- indomethacin

agents that are more COX2 selective

- acetaminophen

- meloxicam

- celecoxib

- diclofenac

NSAIDs: Salicylates

- MOA: non-selective inhibition of COX enzymes (main difference is the level of selectivity)

- Many are OTC

- oral, topical

cautions: GI, renal, blood side-effects (Similar side-effects for all classes of NSAIDs due to MOA)

Acetylated salicylates (non-selective)*******

covalent, irreversible inhibition of COX enzymes (other classes are NOT covalent and irreversible)

Non-acetylated salicylates*******

noncovalent, reversible COX inhibition

Side-effects and therapeutic effects are associated with the presence of....

carboxylic acid group

What is required for therapeutic activity

- ortho-hydroxyl

- ortho-ester group

Aspirin:

TC:

PC/MOA:

CC:

- TC: analgesics & anti-inflammatory

- PC/MOA: COX inhibitor (non-selective)

- CC: salicylate (salt or ester of o-hydroxybenzoic acid)

Fenamates/fenamic acids (N-arylanthanilic acids)

TC:

PC/MOA:

CC:

- TC: analgesic & anti-inflammatory

- PC/MOA: COX inhibitor (non-selective)

- CC: fenamic acid (N-arylanthranilic acids)

NSAIDs: Acetic acid agents*****

- diclofenac

- indomethacin

Metabolic activation of the acetic acid prodrugs

NSAID: Acetic acid

TC:

PC/MOA:

CC:

TC: analgesic & anti-inflammatory

PC/MOA: COX inhibitor (non-selective)

CC: acetic acid (or benzeneacetic acid)

NSAIDs: propionic acid*****

- largest group of NSAIDs

- S is more potent than R, but we use the racemate because they are interchangeable in body

- ibuprofen, naproxen

Propionic acid

TC:

PC/MOA:

CC:

- TC: analgesic & anti-inflammatory (antipyretic)

- PC/MOA: COX inhibitor non-selective

- CC: propionic acid

NSAIDs: Oxicams (enolic acids) MOA

- inhibit COX enzymes

- also inhibit the migration of leukocytes to inflamed areas & the release of lysosomal enzymes from these cells

- meloxicam

SAR of oxicams

- tautomeric enol

- ring N-methyl group

- N-heteroaryl carboxamide

Oxicams

TC:

PC/MOA:

CC:

- TC: analgesic & anti-inflammatory

- PC/MOA: COX inhibitor (non-selective)

- CC: oxicam

NSAIDs: Coxibs*****

- selective for inhibition of COX2

- celecoxib (first COX2 selective inhibitor)

Why were rofecoxib and valdecoxib withdrawn from the market?*****

high risks of serious CV events

Coxibs

TC:

PC/MOA:

CC:

- TC: analgesic & anti-inflammatory

- PC/MOA: COX2 inhibitor

- CC: diaryl-substituted pyrazole

NSAIDs: Pyrazolones

- antipyrine

- not widely used

- no COOH group present, unlike other NSAIDs

- relatively selective to COX3

Agents used for neuropathic pain

- SNRIs

- TCAs

- Calcium channel inhibitors

- Sodium channel inhibitors

- Opioids

- NMDA receptor antagonists

Agents that are Calcium channel inhibitors

- gabapentin (Neurontin),

-pregabalin (Lyrica)

ADMET of pregabalin

A: well-absorbed orally

E: primarily renally

T: dizziness, somnolence, dry mouth & edema are among the most common SEs/ADRs

CCIs

TC:

PC/MOA:

CC:

TC: analgesic (and anti-epileptic)

PC/MOA: alpha2-delta ligand

CC: GABA analog

Agents used for headache & migraine

- adrenergics (BB), propranolol

- GABAergics, barbiturates (butalbital)

- serotonergics, triptans (sumatriptan)

- CGRP inhibitors, MABs, small molecules (ubrogepant)

GABAergics: agents, MOA, and ADMET

- butalbital

- GABAergic (positive allosteric modulator that enhances GABA activity)

- CNS effects (sedation), potential for addiction

Serotonergics: Triptans

- family of tryptamine-based drugs for treating migraines and cluster headaches

- agents: sumatriptan

- SAR: similar to serotonin, N-substituents

Serotonergics ADMET

A: more lipophilic agents (eletriptan) have better CNS penetration, but more CNS effects

M: several have active metabolites

T: contraindicated in several CV diseases; risk of serotonin syndrome if not used with other serotonergic agents

Serotonergics

TC:

PC/MOA:

CC:

TC: antimigraine agent

PC/MOA: 5-HT1B/5-HT1D receptor agonists

CC: indoethylamines

Calcitonin gene-related peptide (CGRP) inhibitors

- signaline system that plays a key role in migraine pathophys

- MABs

- ubrogepant

- cost/insurance coverage is a limiting factor

What is a key advantage of the gepants compared to the triptans?*****

They lack the vasoconstrictive effects of the triptans

Topical/local anesthetics

- the "caines"

- capsaicin

- block sodium channels in peripheral sensory neurons, preventing impulse transmission

- for temporary relief of pain or itching

SAR structure of Caines*****

- ester core (benzocaine)

- amide core (lidocaine)

- Hydrophobic/lipophilic portion

- Basic amine/hydrophilic portion

- not ALL compounds fit this SAR model

ADMET of topical agents

A: applied topically to mucous membranes or skin, oral BA isnt an issue

M: hydrolysis of ester or amide bonds, N-dealkylation of N-substituted amides

E: primarily in urine

ADRs of topical agents

- convulsions

- CNS depression

- CV effects (especially in amide-based agents)

- methemoglobinemia

- hypersensitivity to p-aminobenzoic acid (PABA

Precautions of topical agents*****

Patients with a history of hypersensitivity to any local anesthetic (“caine”) agents, especially PABA-based agents

Capsaicin

- topical

- OTC

- anaglesic, but also an irritant (used in many pepper sprays)

- binds to TRPV1 (vanilloid) receptor. Causes depletion of substance P

T/F: Capsaicin works well for arthritis of "deep" joints

FALSE

Capsaicin is typically used as...

add-on therapy w/other agents

Identify which of the agents belong to NSAIDs:

A. Methylprednisolone

B. Aspirin

C. Ibuprofen

D. Celecoxib

E. Pregabalin

B. Aspirin

C. Ibuprofen

D. Celecoxib

T/F: Increasing steric bulk on the N atom flips activity from μ agonist to μantagonist

TRUE

Which metabolite is responsible for the hepatotoxicity of acetaminophen?