Opiates + Opioids

1. - air dried milky exudate

2. - unripe capsule seed

3. ___________ contains 10-10.5% morphine

4. ___________ camphorated opium tincture

5. ___________ opium tincture or deodorized opium tincture

1. opium

2. poppy capsule

3. powdered opium USP

4. paregoric

5. laudanum

1. ___________: any natural or synthetic agent derived from, or structurally related to morphine

2. ___________: opium-like or morphine-like, with reference to a drug’s pharmacological activity (includes enkephalin peptides and endorphins, which are not structurally related to morphine)

3. ____________: neuronally located proteins to which opioid agents bind to + elicit a biological response

1. opiate (structurally related)

2. opioid (acts like)

3. opioid receptors

1. Morphine belongs to a group of medicines called _________ ________ and acts on the CNS at opioid receptors

2. Bioavailability of oral morphine is only about ______% and has many unwanted side effects

3. ER caps/tabs should NOT be used for ________ pain

1. narcotic analgesics

2. 30%

3. acute

Morphine + Side Effects

1. Produces several serious limitations as a drug molecule → 5

2. Methylation of phenolic OH of morphine gives __________ (will decrease analgesic, physical dependence, resp depress, etc)

1. addictive, resp depression (high doses), emetic (N/V), GI, tolerance

2. codeine

The greater analgesic activity of heroin may result from a combination of more rapid brain uptake due to increased ____________ and a rapid brain _________ of the “less active” to “more active” metabolite

lipophilicity, metabolism

Morphine Derivatives SAR

+analgesic activity

1. ________ C6 OH (OH to =O) and ____________

2. C6 OH substitution →

3. __________ of C6 OH group

4. Conversion of C6 OH to an ________

REQUIRED for analgesic activity

5. -

6. -

1. Oxidation, reduce C7/8 double bond

2. H, Cl, or F

3. esterification

4. ether

5. C3 OH

6. tert amine in piperidine ring

1. _____ activity

2. imparts _________ activity

3. Replacing N-methyl group with a HYDROGEN ______ activity

1. +

2. antagonist

3. -

The potent “oxy” analogues:

Oxycodone and Oxymorphone → examples of analogs containing the …

C14 OH + C6 ketone (oxidation)

___________________: increase in analgesia compared to morphine/codeine – examples of 7,8-double bond reduction and C-6 hydroxyl group oxidation → keto group

hydrocodone, hydromorphone

Two well-known analgesic opium alkaloids are present in the seed capsule exudate of the opium poppy. What are they?

morphine, codeine

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

phenanthrene

What is the name of this highly addictive synthetic morphine analog?

How is it obtained from morphine?

heroin, acetylation C3 + C6 phenols

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

respiratory depression

Codeine is an analgesic when given orally but has NO analgesic activity when given by intracerebral injection. Why?

prodrug → must be activated in liver

What two modifications to the morphine molecule improved analgesic potency and are both present together in the hydromorphone molecule?

C6 oxidation, C7/8 = reduction

What common structural feature do oxycodone and oxymorphone both have that is not present in the structures of hydromorphone and hydrocodone?

C14 OH

__________________: sections of the morphine molecule are cut away in order to determine which parts are essential for analgesic activity, and which parts are superfluous (unnecessary)

molecular trimming

“Molecular Trimming” of the Morphine Molecule

1. D ring removed → _________ are obtained, ex: levorphanol. levomethorphan → characteristic?

2. Half of C ring removed → ___________ → analogs = cyclazocine, pentazocine → characteristic?

3. Cut away B ring → __________ → characteristic?

4. Open piperidine ring → dextropropoxyphene (________) and ________

1. morphinans → 3-4x more potent

2. benzomorphan → mixed agonist/antag

3. demerol → 10-12% potency

4. Darvon, methadone

1. How many fused rings are missing in the Morphinan-based analgesics Levorphanol and Levomethorphan?

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

1. 1 (D ring)

2. 2 (C and D)

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

Demerol/meperidine

SAR considerations for opioid analgesics

1. An __________ ring bound to a _________ carbon

2. A __________ _________

3. The ^ is separated from the quat carbon by ____ carbon atoms

4. Four substituents, R1-R4, CANNOT BE _____

1. aromatic, quaternary

2. tert nitrogen

3. 2

4. H

MORPHINANS

1. Levorphanol interacts w ___________________ receptors → _____x more potent

2. Levomethorphan causes dysphoria, psychotomimetic effects + hallucinations → ______x more potent

3. Dextromethorphan used as an ___________ → _________ at HIGH DOSES

4. N-methylmorphinan was the 1st one synthesized → weak analgesic due to ___________________

5. Butorphanol tartrate → ____________, 5x more potent → ClnCON:

6. ^ Why does butorphanol act as a partial agonist at opioid receptors?

1. NMDA Gly + GABA, 6-8x

2. 5x

3. antitussive, hallucinogen

4. absence of C3 OH

5. partial agonist, do not use in CHF/MI

6. bulky N substituent

BENZOMORPHANS (D ring + ½ C ring removed)

1. First series to show any significant separation of analgesic activity from ________ __________

2. *MOST ACTIVE BENZOMORPHANS possess ___________________

1. dependence liability

2. C2 OH, C5 + C9 dimethyl

Benzomorphans (cont)

1. Phenazocine (Prinadol) →

2. Cyclazocine →

3. Pentazocine (Talwin) tab + injectable →

1. no longer marketed in US

2. not available in US, 1st drug effective in heroin addiction tx

3. mod-severe pain (1/6 to 1/3 potency of morphine)

Meperidine (Demerol)

1. ______x as potent as morphine

2. Synthesized in an effort to find an ________________

3. ____________ may occur when used with a MAOI

4. Meperidine (N-CH3) → __________ (N-H) TOXIC metabolite limits the use of meperidine to short-term treatment!

1. 0.1x

2. atropine substitute

3. serotonin syndrome

4. normeperidine

___________ → “reverse esters” of meperidine → ILLEGAL!

prodines

Possibly by-products of PRODINE SYNTHESIS

1. _________ in the brain causes oxidation of MPTP → MPDP+ → MPP+

2. MPP+ toxic metabolite → inhibits ________ uptake + destroys neurons in substantia nigra → causes ______________________

1. MAO(B)

2. DOPA, irreversible Parkinson effects

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

Broke the pharmacophore rules of opiates!

fentanyls (-fentanils)

Which drugs are 100-200 times more potent than morphine, is used in anesthesia and affords rapid onset and rapid post-operative recovery?

A. sufentanil

B. alfentanil

C. carfentanil

D. remifentanil

E. fentanyl (Sublimaze)

D + E

(sufentanil - 1000x morphine → labor and delivery
alfentanil - 25x morphine

carfentanil - 10,000x morphine → horse tranquilizer)

What Fentanyl-like drug is 10,000 times more potent than morphine, is used as a large animal tranquilizer?

A. sufentanil

B. alfentanil

C. carfentanil

D. remifentanil

c

METHADONE (NO fused rings)

1. Racemate → ___ isomer MOST potent

2. MOA:

3. _______ acting than morphine

4. ^ due to active metabolites → name them (3)

5. Blocks _____ effects of subsequent doses of opiates + blocks ______________ of addicts

1. R

2. u-agonist

3. longer

4. a-methadol, LAAM, N-demethylation products (1°, 2° active)

5. euphoric, drug-seeking behavior

T or F:

The secondary amine metabolites have shorter half-lives than methadone.

F (longer)

______ and ______ are plasma biomarkers used to identify drug abuse OR for compliance w drug abuse therapy

EDDP, EMDP

Dextropropoxyphene is a structural variant of methadone (+________ group) that was a widely used analgesic both in the US + Europe UNTIL it was found to have life-threatening _________ effects → MOA: ________ u-agonist → Potency = __________ of morphine

phenyl, cardiotoxicity, weaker, 1/12

Tramadol (Ultram)

1. Prodrug →

2. For tx of ___________ pain

3. Exhibits ______ affinity for u, k, and delta receptors

1. remove CH3 to activate

2. mod-severe

3. equal

_________ was the first clinically useful opioid receptor ANTAGONIST that has partial agonist effects due to its bulky N substituent

Nalorphine

The severely trimmed down morphine analog methadone can be used for severe pain; what other indication can Methadone be used for?

addiction

What is the primary metabolite(s) of methadone? Does it have analgesic activity?

a-methadol, LAM, yes

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

Must undergo ________ for good analgesic activity

metabolism (P1 oxidative demethylation)

How is the morphine antagonist NALOXONE different from Nalorphine?

1. Both are pure ____________

2. Antagonist selectivity:

3. Structural differences:

1. antagonists

2. Naloxone: u > k > delta, Nalorphine: u = k > delta

3. C14 OH, reduce C7/8 =, C6 ketone

What is the drug of choice for reversing opioid-induced respiratory depression?

Naloxone (Narcan)

Methylnaltrexone Bromide (Relistor)

1. _________ acting opioid receptor antagonist (NON-CNS ACTING)

2. Targets the __________ (cannot pass GI memb or BBB)

3. Uses: 2

1. peripherally

2. GI tract

3. OIC (opioid induced constipation), chronic non-cancer pain

Buprenorphine (Buprenex)

1. MOA:

2. ______x potency morphine

3. Use:

4. Tx for opioid dependence in combination w naloxone = ____________

5. Exhibits _____ receptor dissociation kinetics

1. partial u-agonist

2. 20-50x

3. mod-severe pain

4. Suboxone

5. slow

Suboxone for Opioid Dependence

(Buprenorphine + Naloxone combination drug)

1. Buprenorphine → u-agonist + k-antagonist → limitations?

2. Naloxone → pure ________

3. Suboxone → produces _________ symptoms when INJECTED → reduce parenteral misuse, tx of opioid addiction

1. u-agonist limited by ceiling effect at higher doses

2. u-antagonist

3. withdrawal

Why is the design of Methylnaltrexone Bromide, a quaternary ammonium bromide salt, appropriate considering its therapeutic use?

salt = polar = cannot pass memb = stuck in GI

What features did the Beckett and Casey model of the mu-receptor describe for the binding of morphine?

1. _______________, such as meperidine and methadone, took on similar shape to that of morphine when binding to the u-receptor

2. Proposed that newer u-agonists (eg. the ____________) that did NOT resemble morphine did not fit this model

1. non-rigid opioids

2. fentanyls

Original model of the u-opioid receptor proposed (Beckett + Casey)

name the parts

1. cavity

2. anionic site

3. H bond acceptor site

4. flat lipophilic surface

Why did Portoghese formulate his Bimodal Model of the mu-receptor?

→ Reason: If all opioids bind to the receptor in the same conformation + same surface area, then they SHOULD contribute the SAME _____________________

Thus, his bimodel receptor binding model proposed that different opioid series (RIGID OR NON-RIGID) bind to different surface areas of the SAME receptor protein

analgesic effect

T/P Subsite Receptor Model

accommodates binding of both morphine analogs + natural enkephalin peptides

1. P-subsite represents → _______ of enkephalin

2. T-subsite → binds _____ of enkephalin

3. Thus …

1. phenylalanine

2. tyrosine

3. rigid opioids → T-subsite, non-rigid opioids → P-subsite

Which subsite would you expect morphine to interact with in the T/P subsite model?

T

(remember tyrosine structure → aromatic ring + OH

phenylalanine → just aromatic ring)

Opioid Receptors

1. Mu (u) receptor → Principal pain-modulating site in CNS, ______________ → 2 subtypes

2. Kappa (k) receptor → mediates ___________ with DECREASED addiction liability + respiratory depression → appears to be coupled to ______ receptor → implicated in ____________ side effects of opiates

3. Delta (δ) receptor → usually stimulated by the _________ → may have a role in … (4)

1. morphine selective, m1 = analgesic, m2 = resp depress

2. sedating analgesia, sigma, psychotomimetic + dysphoric

3. enkephalins, GI motility + mood + behavior + cardiovasc regulation

Does Fentanyl bind to the same site on the mu-receptor as Morphine or at a different site?

diff

Endogenous Opioid peptides

1. what kind of molecules are the enkephalins?

2. what are the other analgesic peptides?

3. Enkephalins are _____________ (NOT derived from hydrolysis of endorphins)

4. Where are endorphins found?

5. ___________ promotes GH and PRL release

6. Endorphins + enkephalins may be ________________ → Gi/G0 type GPCRs → 3 effects

1. peptides

2. endorphins, dynorphins, neoendorphins

3. widespread in CNS

4. hypothalamus, pituitary gland

5. b-endorphin

6. inhibitory → analgesia, inhib DOPA, inhib ACh

What are the three distinct families of endogenous opioid peptides?

endorphins, enkephalins, dynorphins

Enkephalinases: 6 types, FUNCTION =

hydrolyze + inactivate enkephalins

Opioid peptide SAR

1. All endogenous opioid peptides have ___________________________

2. The _______ is essential for activity

3. ^ may be alkylated →

4. Bulky groups (eg. addition of N-methyl to Phe) does what?

1. Leu or Met enkephalin as first 5 AA residues

2. Tyr1

3. methyl - agonist, allyl - antag

4. +resistance (against peptidases)

Endorphins and opioid receptors in the ____________ of the spinal cord, ________, and _________ (PAG) areas are associated with the transmission of pain signals

dorsal horn, thalamus, periaqueductal gray

OPOID RECEPTORS:
Name 3 types + the preferred endogenous ligands

1. mu → endorphins, enkephalins, truncated forms of dynorphin

2. kappa → dynorphins/neoendorphine

3. delta → enkephalins (ONLY SLIGHTLY)

Compared to Morphine, how potent of an analgesic is Met enkephalin?
(more or less?)

less ~1/33

1. What kind of receptors + ligand type are opioid receptors? (u, k, δ)

2. What happens when an opiodi agonist binds to m-receptor? Activation of _________

1. GPCR → Gi,G0 (inhibitory)

2. protein kinase A