Term
| examples of natural opioid products |
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Definition
[image]
high lipophilicity
tertiary amine has a pKa ~9 (the tertiary amine will be IONIZED in vivo)
basic molecules with a good logP to cross the BBB and bind to the target receptor |
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Term
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Definition
opiate: describes any natural or synthetic agent derived from morphine
opioid: opium, or morphine, like in terms or pharmacological actions |
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Term
| common 5 amino acids in endogenous opioids |
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Definition
Tyr-Gly-Gly-Phe-Met
Tyr-Gly-Gly-Phe-Leu |
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Term
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Definition
as a group are called endorphins
beta-endorphins
dynorphins
endomorphins |
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Term
| opioid peptides analgesic action |
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Definition
spinal and suprasinal sites
peripheral mechanism of action associated with the inflammatory process
in the CNS: inhibitory neurotransmitter or neuromodulator action on afferent pain signaling neurons in the dorsal horn of the spinal cord and/or interconnecting neuronal pathways |
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Term
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Definition
mu, kappa, delta
GPCRs
highly conserved (each receptor subtype is very similar) |
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Term
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Definition
[image]
recognize positions 3, 6, 7&8, 14, 17
prototype for opioids
selective for mu
stereospecific - only (-)
the receptors must also be stereospecific |
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Term
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Definition
[image]
modifications can be done at positions 3, 6, 17 and the double bond at 7-8
properties than can be affected by these changes:
selectivity
affinity
agonist/antagonist
physicochemical properties
pharmacokinetic properties |
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Term
| pharmacophore of morphine |
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Definition
[image]
in red is the pharmacophore: phenyl ring and piperidine ring
the piperidine ring does not have to be a ring, it can be open
need the phenyl ring and the tertiary amine (the distance cannot be defined by the number of carbons) |
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Term
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Definition
[image]
removal of ring E
levo: opioid activity
dextra: antitussive
commercially available morphinans:
levorphanol (R = CH3): mu agonist
butorphanol (R = cyclobutyl): k agonist and mu antagonist |
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Term
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Definition
[image]
removal of ring C and E
commercially available:
pentazocine: weak mu antagonist and k agonist
most of the small molecule analogs have lower affinity for the receptors than morphine |
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Term
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Definition
[image]
meperidine (R = CO2C2H5; ester)
mu agonist
short duration
may have higher affinity than morphine |
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Term
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Definition
[image]
commercially available: fentanyl, sufentanyl, alfentanyl, remifentanyl
mu agonists
anilidopiperidines are not directly related to morphine
SAR:
isosteric replacement of the phenyl ring
substitution of the 4 position (piperidine ring)
substitution of the 3 position (piperidine ring) is TOLERATED, but may not improve or increase activity |
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Term
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Definition
[image]
open chain compounds
methadone:
long duration
modifications in the structure are detrimental |
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Term
| SAR of morphine derivatives |
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Definition
NITROGEN ATOM
[image]
tertiary amine is required
modulates potency: determines if the molecule is an agonist or an antagonist
agonist vs. antagonist properties:
CH3 = agonist
3-5C = antagonist
unsaturation and small carbocyclic rings = antagonist
large substituents = agonist
3-PHENOLIC OH
[image]
H decreases activity
OCH3 (ether) decreases activity
OCOCH3 (ester) decreases activity
codeine has antitussive activity: has an ether (low analgesia); metabolized can be dealkylated to an OH (analgesic activity)
6 OH
[image]
H increases activity
OCOCH3 (ester) increases activity
keto decreases activity (increased if 7-8 double bond AND a 6 keto)
C RING
[image]
7-8 dihydro (single bond) increases activity
6 keto decreases activity
hydromorphone (6 keto and 7-8 single bond) = more active
14 OH increases mu agonist affinity and decreases antitussive activity |
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Term
activity of heroin
[image] |
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Definition
[image]
semisynthetic analog
low mu affinity
higher lipophilicity
in vivo it will have a higher potency b/c more heroin will be going to the brain and available for binding
heroin can be quickly metabolized to morphine |
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Term
etorphine
[image]
receptor activity?
potency? |
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Definition
[image]
agonist
more potent than morphine |
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Term
buprenorphine
[image]
receptor activity?
potency? |
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Definition
[image]
partial agonist/antagonist
more potent than morphine |
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Term
diprenorphine
[image]
receptor activity?
potency? |
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Definition
[image]
antagonist
more potent than morphine |
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Term
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Definition
[image]
lipophylic site: where the aromatic ring binds
anionic site: where the tertiary amine binds
cavity for C15 and C16
additional liphophylic site
[image]
[image]
H bond acceptor site if the the OH of the phenyl ring
[image]
A = enkephalin: portion where the OH group of the phenyl ring binds; also binds to the second liphophilic region
B = morphin: binds at the phenoxy site
C = flexible molecule, binds to a different site
based on enkephalin binding, there are 2 places where the aromatic ring can fit |
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Term
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Definition
[image]
rigid structures
3-OH
N-allyl, N-cyclopropylmethyl, N-cyclobutylmethyl
true antagonists = naloxone and naltrexone
buprenorphine is a partial agonist/antagonist
no double bond at 7-8 increases affinity |
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Term
| SAR for kappa receptor agonists/mu antagonists |
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Definition
[image]
[image]
agonistic effects at kapp:
phenyl ring with OH group
tertiary amine the correct distance away
salvinorin A is derived from a plant
illegal in many states b/c it is a hallucinogen
very high affinity for kappa, very selective for kappa |
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Term
metabolism of codeine
[image] |
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Definition
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Term
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Definition
most endogenous peptides have enkephalin as the first AAs
Tyr essential for endogenous opioid peptides
Phe essential (phenyl group)
last 3 AAs can be changed
conformations -> several low energy conformation
D-AA increase resistance to aminopeptidases
conversion of terminal COOH -> resistant to carboxypeptidases
bulky or unnatural AA changes conformational energy
rigidity -> increased selectivity |
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Term
| comparison of commercially available opioids |
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Definition
[image]
hydromorphone: compared to morphine has higher affinity (b/c single bond and 6-keto); agonist b/c methyl group at 17
oxymorphone: agonist b/c of methyl at 17; higher affinity than hydromorphone (OH group at position 14 = increased affinity)
hydrocodone: lower affinity than hydromorphone b/c of ether at 3
nalbuphine: antagonist; will have high affinity (single bond at 7-8, OH at 14) |
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Term
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Definition
selectively binds to N-type potential dependent Ca channels
analgesic effect results from blockade of the NT release and a disruption of normal nociceptive signal transmission
use for treatment of severe chronic pain
intrathecal administration
peptide containing 25 AAs
NOT an opioid analog
peptidomimetic |
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