Analgesics – anodyns = opioid = „strong“ = „narcotic“
analgesics
©Oldřich Farsa 2019
Opioid receptors
● 4 main types: μ, κ ,δ and ORL-1
●
( receptors currently not recognized as
opioid)
● every type has several subtypes
● μ receptor activation leads to analgesic
activity, breathing attenuation etc.
● κ receptor activation: also analgesic activity,
takes part in diuresis and neuronal activity
regulation
● δ receptor activation: also analgesic activity,
attenuation of breathing and peristalsis of
GIT
μ receptor
● opens ion channel in cell membrane
●
K+
can stream into the cell  decrease of neurone
excitability
● also decreases input of Ca2+
into terminal nerve which
decreases neurotransmitter release
κ receptor
●
directly linked with Ca2+
channel
● binding of an agonist to the receptor causes
channel closing
● inhibition of all nociceptive signals
● activation leads to myosis, diuresis, analgesia and
dysphoria
δ Receptorδ Receptor
● not linked with any ion channel
● activation of the receptor probably leads to a change
of adenylate cyclase geometry  active site closure
● activation leads to pain relief, attenuation of
breathing and peristalsis of GIT
ORL-1 receptor
●also „orphan“, discovered quite recently
●natural agonist nociceptine = orfanine (peptide)
●linked with many activities: memory, cardiovascular
functions, kidneys
●probably ifluences dopamine concentrations in CNS and
is involved in neurotransmitters release in anxious
conditions
Natural opioid receptors agonists – endogenous analgesics
●
morphine receptors exist athough it is not endogenous  body own opioids must exist!
●
all endo-opioids are fragments of -lipotropin, adenohypophyse hormone consisting of 91
amino acid rests which has no opioid effects
Encephalins – binding preferably to -receptors
Metencephalin H-Tyr-Gly-Gly-Phe-Met-OH
Leuencephalin H-Tyr-Gly-Gly-Phe-Leu-OH
●pentapeptide, all activities of morphine, occurs in all animals including man
Endorphins (= „endo-morphines“) - : 16 AA
: 31 AA – after i.v. application has morphine effects
in CNS
: 17 AA
●
-lipotropin is not direct precursor of opioid peptides; more precursor peptides exist:
preproencephaline A  encephalins
preproopiomelanocortine  endorphines
preproencephaline B  dynorphines
Dynorphines – peptides from 8 -32 AA, analgesic effect, neurotransmitters in CNS, functions
not completely clear
Endorphines and encephalins as parts of -lipotropine sequence
CH3CH3
N
O
CH3
N
O
N
O
N
O
N
N
O
NO
CH3
CH3N
O
NO
N
O
CH3
CH3
NO
N
O
N
O
NO
N
O
O
N
O
N
N
O
OO
N
O
O
N
O
N
O
S
CH3
N
O
NO
N
O
NO
N
O
CH3 O CH3 O
CH3
CH3
CH3
O
O
N
CH3
CH3
O
N
N
O
N
N
O
O
N
CH3
O
N
NNH
O
N
N
O
N
N
O
N
O
N
N
O
O
O
H
H
HH
H
HH
H
H
H
H
H
H
H
H
H
H
H
H
HH
H
H
H
H
H
H
H
H
H
H
H
H
H
H H
H
H
H
H
H
H
H
H
H
H H
H
H
H
H
H
H H
H H
H
Primary structure of -endorphine
Dynorphine A sequence (1 - 18)
H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-
5
Arg-Pro- Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH
10 15
NH
NH
H
NH
HNH
HNH
HNH
H
NH
O
NH
O
NH
H
OH
NH2
O
O
CH3
CH3
O
NH
NH
NH2
O
NH
NH
NH2
O H
CH3
CH3
O NH
NH
NH2
O
H
NH
H
NH
H
NH
H
O
OH
NH2
O
CH3
CH3
O
NH2
O
Primary structure of dynorphine A (1 – 13) - swine
Opium
●dry milky juice (latex) from immature poppy heads (Papaver somniferum)
●
known from Assyrian manuscripts from 7th
century b. C.
●contains 20 – 25 % alkaloids: morphine 3 – 23 %, narcotine 2 – 12 %, codeine 0.3 –
3 %, papaverine 0.8 – 1.2 %; in sum up about 40 various alkaloids
●morphine the most important
●alkaloids in form of salts with carboxylic acids; meconic acid typical
●beaten-out empty dry poppy heads are alternative resource of opium alkaloids (CZ,
SK)
O
O
OH
O
OHO
OH
meconic acid
Morphine and its simple derivatives
12
13 14
9
N CH3
16
15
1011
12
3
4
O
5
6
O 7
8
O
R
1
R
2
A
B
C
D
R1
= R2
= H morphine MSI®
, MST®
, Sevredol®
...
●isolated by Friedrich Wilhelm Sertürner, pharmacist in Paderborn, from opium in 1806
●structure elucidation: 1925 Robinson and Gunland proposed stuctural formula, 1952 Gates
and Tschudi confirmed structure including stereochemistry by means of total synthesis
●basic anodyn isolated from opium or beaten-out empty dry poppy heads
R1
= CH3
, R2
= H codein
●basic antitussive
●semi-synthetic; prepared from morpine by selective methylation of phenolic group
●potencuje účinek slabých analgetik potentiates effect of weak analgesics
● abot 10 % methabolized to morphine
R1
= R2
= CH3
CO diamorphine syn. heroine
●2x more effective than morphine, better penetrates into CNS
●misused as an illegal drug of abuse
Morphine and its simple derivatives: further ethers used as antitussives
12
13 14
9
N CH3
16
15
1011
12
3
4
O
5
6
O 7
8
O
R
H
A
B
C
D
R = CH3
R = O N
ethylmorphine
Diolan ®
pholcodine
Neocodin ®
Effects of opioid analgesics
●analgesic
●
antidiarrhoic ( -,  -receptors in gut)
●antitussive – from attenuation of caugh reflection to expiratory centre inhibition
●euphoriant
●physical addiction – very slowely formed during relieving of strong pain
Semi-synthetic morphine and codeine derivatives
H
H
N
CH3
O
H
O
OR
H
N
CH3
O
H
O
O
CH3
OH
R = H hydromorphone
●10x more active than morphine
Jurnista®
, Palladone®
cps. ...
R = CH3
hydrocodone
●more effective antitussive than codeine
oxycodone
●2x less active analgesic than
morphine; faster onset of action
●antitussive
Oxycodon (firm)®
tbl..
Semi-synthetic morphine and codeine derivatives
H
N
O
H
H
OH
OH
OH
nalbuphine
Nalbuphin®
OrPha inj.
●short period treatment of medium to strong pains, before- and post-operating analgesia
Oripavine derivatives
H
NO
H
O
CH3
H
CH3
CH3
CH3
CH3
OH
OH
H
N CH3
H
O
OH
O
CH3
oripavine
●alkaloide from Papaver orientale
buprenorphine
●relief of non-malignant pain of medium
intensity
●opioid withdrawal therapeutic programs
Norspan®
emp. tdr., Transtec®
emp. tdr.
H
H
N
CH3
O
CH3
H
H
N
CH3
O
R
dextromethorphan
Dextrometorphani hydrobromidum
monodydricum PhEur
●antitussive
●euphoriant in higher doses
Humex ® , Robitussin ® , Stopex ® ,
Tussidril ® - OTC
R = H levorphanol
●better analgesic than morphine
R = CH3
levomethorphan
Morphinane derivatives
Morphinane derivatives (continued)
OH
H
N
OH
butorphanol
●treatment of moderate to severe pain
●
a potent -receptor agonist and an antagonist at -receptor
●
intensive hepatic first-pass metabolism  parenteral administration (nasal sprays)
Benzomorphane derivatives
●
removal of the C-ring  greater afinity for -receptor; weak for -receptor
●
central C-atom remained quarternary  truncated open analogues of the C-ring
C
H
H
N
CH3
CH3
OH
CH3
CH3
A
B
D
H
H
N
OH
CH3
CH3
C
H
H
N
CH3
CH3
OH CH3
CH3
=
pentazocine
●treatment of moderate pain
Fortral®
tbl., inj. sol.
phenazocine
Phenylpiperidine derivatives and compouds derived from them
●originated by removal of the B,C and E rings which are not necessary for the activity
●faster onset and shorter lasting of action
●remaining AE: addiction, expiratory centre attenuation
O
CH3
O
N
CH3
N
N NH2
O
N
pethidine
syn. meperidine [USAN]
Dolsin ® inj. sol.
piritramide
Dipidolor ® inj.
●better toxicity profile
●1st
choice in
postoperative pain
management in EU
CH3
N
N
O
Phenylpiperidine derivatives and compouds derived from them
4-anilidopiperidines: fentanyl
fentanyl
Fentanylum PhEur (free base) – transdermally
Fentanyli citras PhEur – i.m., i.v.
Durogesic ® derm. emp. tdr.
Phenylpiperidine derivatives and compouds derived from them
Fentanyl analogues - 4-anilidopiperidines
N
CH3
O
N
S
O
CH3
N
N
N
N
CH3
N
N
O
O
CH3
CH3
O
N
CH3
O
N
O
CH3
O
O CH3
O
sufentanyl
●also in anaesthesia
Sufenta
inj.
alfentanyl
Rapifen
inj.
remifentanyl
Ultiva
inj.
●so called opioid anaesthetics (combined with propofol, ketamine)
Phenylpropylamine derivatives
●can be derived from 4-phenylpiperidines by formal deleting of one
methylene group of piperidine ring
●structurally related to fluorene-9-carboxylic acid
●the most simplified structures still to have opioid receptor activity
●activity comparable to morphine
●efficient p.o.
●less AE than morphine
methadone
●withdrawal symptoms less
severe and more gradual as
compared to morphine  opioidwithdrawal
therapeutical
programs
Methadon Zentiva ® oral solution
H
N
CH3
CH3
CH3
CH3
O
O
CH3
O
H N
CH3
CH3
CH3
OH
O
O
CH3
O
H N
CH3
CH3
CH3
dextropropoxyphene
●substitution of one
phenyl with benzyl  2nd
chiral centre
(+)-(2S, 3R)-analgesic;
1/10 of methadone
activity
Darvon ® (USA)
levopropoxyphene
(-)-(2R, 3S)-antitussive
Novrad ® (USA)
Structure-activity relationships (SAR)
●an aromatic ring and a basic nitrogen atom are necessary for action, a phenolic group is
not( the rings B, C, D and E of the morphine skeleton are not necessary for analgesic
action)
●quarternary (tetrasubstituted) C(4) of piperidine derivatives is necessary in the frame of this
group, with exception of fentanyl
●substitution of methyl at nitrogen in D ring of morphine: to allyl leads to antagonists (equatorial
position), to phenethyl leads to agonists; explanation by presence of 2 different hydrophobic
binding sites
●-OH group at C(14) supports the placement of a substituent into equtorial position; this moiety
as a steric hindrance orients into equatorial position also other substituents than allyl (e.g.
cyclopropylmethyl)
N-substituted morphine derivatives acting as agonists and antagonists – a model of interaction
with a receptor
Morphine receptor antagonists with -OH group at C(14)
●-OH group is a steric hindrance which supports to dominancy of the equatorial
position of allyl
Morphine receptor antagonists
H
N
O
H
O
OH
OH
CH2
H
N
O
H
O
OH
OHH
N
O
H
OH
CH2
OH
naloxone
Naloxoni hydrochloridum
dihydricum PhEur
●i.v. administration only;
extensively
methabolised in liver
Naloxone WZF ® Polfa
nalorphine
naltrexone
Naltrexoni hydrochloridum
PhEur
●p.o.
●useful also in treatment of
alcoholism (blocks binding
of endoopioids)
Revia ® por tbl flm
●antidots in opiates overdosage