MedChem Jones

What are the two well-known analgesic opium alkaloids present in the opium poppy seed capsule exudate?

Codeine and morphine.

What common tricyclic aromatic ring system scaffold are morphine-related drugs based on?

Phenanthrene.

How is heroin obtained from morphine?

Acetylation of the C3 and C6 phenolic groups.

What side effect of morphine is responsible for most patient deaths?

Respiratory depression.

Why is codeine an analgesic orally but inactive when given by intracerebral injection?

Codeine must undergo oxidative O-demethylation to morphine in the liver

What two modifications to morphine improve analgesic potency and are both present in hydromorphone?

1) Reduction of the 7,8-double bond. 2) Oxidation of the C6 hydroxyl group.

What structural modification to morphine usually results in antagonist activity?

Replacement of the N-methyl group with a small bulky alkyl group (e.g., allyl or cyclopropylmethyl).

What structural feature do oxycodone and oxymorphone share that hydromorphone and hydrocodone do not?

A beta-hydroxy group at position 14.

What is meant by "molecular trimming" of the morphine molecule?

Removal of molecular fragments to determine which parts are required for analgesic activity.

How many fused rings are missing in the morphinan-based analgesics levorphanol and levomethorphan?

One (the D-ring).

Why does the morphinan analog butorphanol act as a partial agonist?

It contains a small bulky group on the nitrogen (cyclobutylmethyl).

How many fused rings are missing in benzomorphan-related morphine analogs?

Two (C and D rings).

Which severely trimmed morphine analog was not initially designed as a morphine prototype but still has 1/10th the potency of morphine?

Meperidine.

What are the minimal structural features necessary for opioid analgesic activity?

An aromatic ring bound to a quaternary carbon, a tertiary nitrogen, and a 2-carbon spacer between them.

What extremely potent pain-modulating molecules belong to the 4-anilidopiperidine class?

Fentanyls.

Which fentanyl-like drug is 100–200 times more potent than morphine, used in anesthesia, with rapid onset and recovery?

Fentanyl (Sublimase).

What other indication besides severe pain is methadone used for?

Opiate addiction.

What is the primary metabolite of methadone, and does it have analgesic activity?

α-Methadol (Levo-α-acetylmethadol). Yes, it remains active.

How potent is dextropropoxyphene compared to morphine?

Much weaker

What is unique about the analgesic activity of tramadol when given orally?

It must undergo metabolism (oxidative demethylation) for good analgesic activity.

Why was nalorphine never used clinically as an analgesic?

It causes psychotomimetic effects (hallucinations, confusion).

How is naloxone structurally different from nalorphine?

It has a β-OH at position 14, a reduced 7,8-double bond, and an oxidized C6 ketone.

Why is methylnaltrexone bromide appropriate for its therapeutic use?

Its quaternary ammonium prevents CNS entry, restricting action to the GI tract.

Why is SUBOXONE effective in treating opioid dependence?

It causes withdrawal when injected, reducing parenteral misuse.

What kind of molecules are Met-enkephalin and Leu-enkephalin?

Penta-peptides.

What are the three families of endogenous opioid peptides?

Enkephalins, endorphins, dynorphins.

What role do enkephalinases play?

They enzymatically inactivate enkephalins.

Compared to morphine, how potent is Met-enkephalin?

~1/33 as potent (morphine is 33× stronger).

What type of receptor is the mu-opioid receptor?

A G-protein coupled receptor.

What are the three opioid receptor types?

μ-receptor, κ-receptor, δ-receptor.

What happens when an opioid agonist binds the μ-receptor?

Inhibition of cAMP production → Protein kinase A activation → phosphorylation of cytosolic proteins.

What is the first step in opioid receptor-mediated Gi activation?

Ligand binding causes exchange of GDP for GTP on the α-subunit.

What features did the Beckett & Casey model describe for mu-receptor binding?

A flat lipophilic site with an H-bond acceptor, a cavity, and an anionic site.

Why did Portoghese propose the bimodal model?

Rigid and non-rigid opioids showed different activities inconsistent with the Beckett & Casey model.

Why was discovery of enkephalins linked to the T/P subsite model proposal?

The P-site fits phenylalanine and the T-site fits tyrosine of enkephalins

What do T and P stand for in the T/P model?

T-subsite: Tyr aromatic binding site. P-subsite: Phe aromatic binding site.

Which subsite is morphine expected to interact with?

T-subsite (because of its essential C3-OH similar to tyrosine).

Why is the T/P model consistent with the bimodal model?

Both models allow the basic nitrogen to bind the same anionic site while pivoting to different subsites.

Does fentanyl bind the same site as morphine on the μ-receptor?

No. They bind different subsites despite both binding the anionic site.

What evidence supports fentanyl binding a different site than morphine?

Very different analgesic activity and structural flexibility indicate different subsite interactions.