Neuroleptics = antipsychotics = „major tranquilizers“: drugs for
treatment, or better for attenuation of symptoms of schizophrenic
psychoses
© Oldřich Farsa 2011
Positive SymptomsPositive Symptoms
Hallucinations
Delusions (bizarre, persecutory)
Disorganized Thought
Perception disturbances
Inappropriate emotions
Negative SymptomsNegative Symptoms
Blunted emotions
Anhedonia
Lack of feeling
CognitionCognition
New Learning
Memory
Mood SymptomsMood Symptoms
Loss of motivation
Social withdrawal
Insight
Demoralization
Suicide
Schizophrenia - symptoms
FUNCTION
Historic and alternative treatment of schizophrenia
●insuline coma
●electrocovulsions
●prefrontal lobotomy
● Egas Moniz, 50 000 surgeries, 1935 Nobel prize
● patients were just calmer, but also more sluggish and apathetic
Schizophrenia Pathophysiology
Schizophrenia Pharmacologic
Pathophysiology Profile of APDs
Past Excess dopaminergic Dopamine D2-receptor
activity antagonists
Present
Renewed interest in the Combined 5-HT2/D2
role of serotonin (5-HT) antagonists
Future
Imbalance in cortical More selective antagonists
communication and Mixed agonist/antagonists
cortical-midbrain Neuropeptide analogs
integration, involving
multiple neurotransmitters
dopamine-serotonine
system stabilizer:
aripiprazol
’30s ’40s ’50s ’60s ’70s ’80s ’90s ’00 ‘05
electroconvulsionselectroconvulsions
lobotomylobotomy
insuline comainsuline coma
chlorpromazinechlorpromazine
thioridazinethioridazine
trifluoperazinetrifluoperazine
fluphenazinefluphenazine
perphenazineperphenazine
haloperidolhaloperidol
loxapinloxapin
Typical
antipsychotics
Atypical
antipsychotics
clozapineclozapine
rrisperidonisperidon
olanzapineolanzapine
quetiapinequetiapine
ziprasidonziprasidon
Evolution of therapy of schizophrenic psychoses
HN
H
H
O
O
CH3
O
CH3
O
CH3
O
H
H
H
O
CH3
O
O
CH3
NH
O
CH3
reserpine
●Rauwolfia serpentina
●
inhibition of noradrenaline uptake into storing vesicles ⇒ decrease of catecholamines
levels in both central and periphereal neuronal ends
●antipsychotic
●antihypertensive
●high toxicity
„Typical“ antipsychotics
Phenothiazines with unbranched aminopropane side chain
9
6
8
7
N
10
S
5
2
3
1
4
R
N
CH3
CH3
R = H promazine
R = Cl chlorpromazine Plegomazin®
●Henri Labroit, French military surgeon: causes „artifitial hibernation“
●in therapy since 1953
R = CF3
triflupromazine
R = CH3
CO acepromazine
H. Labroit
Phenothiazines with branched aminoalkane side chain
N
S
R
H
N
CH3
CH3
CH3
R = H alimemazine
R = C≡N cyamemazine
R = OCH3
; R-(-) levomepromazine
Tisercin®
Phenothiazines with 2-(piperidine-2-yl)ethyl side chain
N
S
R
H
NCH3
R = CH3
S thioridazine
●also antimicrobial activity: Mycobacterium tuberculosis, Listeria monocytogenes
●in some developing countries used as an antituberculotic
R = CH3
SO mesoridazine
Phenothiazines with 3-(piperidine-1-yl)propyl side chain
N
S
N
N
OH
periciazine
syn. propericiazine
●AE: hypersensitivity of sensual perception
Perazine series: phenothiazines with 3-(piperazin-3-yl)propyl side chain
S
N
N
N
CH3
R
S
N
N
N
R
OH
R = H perazine
R = CF3
trifluperazine
R = Cl perphenazine
R = CF3
fluphenazine Moditen
Depot®
inj. sol.
Thioxanthenes: isosteric analogues of phenothiazines
9
S
10
8
7
6
5 4
3
2
1
Cl
N
CH3
CH3
9
S
10
8
7
6
5 4
3
2
1
R
N
N
OH
chlorprothixene
●Z-isomer
Chlorprothixen Léčiva®
R = Cl
●mixture E/Z: clopenthixol
●Z-isomer: zuclopenhtixol
Cisordinol®
R = CF3
flupenthixol Fluanxol®
●mixture E/Z
Structure-activity relatioships (SAR) of phenothiazines and thioxanthenes
1. linking chain between N(10) and the basic substiuent:
●
propyl is optimal; compounds with butyl nearly inactive, ethyl ⇒ antihistamine activity
●any substituent in pos. 1 of the side alkyl lowers the activity
●methyl or phenyl in pos. 2 do not decrease the activity while more bulky aliphatic
substituents do
●many various substitutions can be proceeded in pos. 3; basic N is often a part of a ring
2. substituent in pos. 2 of the tricyclic ring
●the highest effect is linked with electron-accepting lipophilic substituents (-Cl, -CF3
,-CN),
activity increases with lipophilicity and electron-accepting properties, electrondor
substituents (-OCH3
, -SCH3
) lower activity
3. tricyclic ring
●disubstitution lowers activity, ring opening completely removes it
●substitution of S with C, O, Se etc. lowers activity; substitution of N(10) lowers activity
except that with alkylidene substituted C(⇒ thioxanthenes)
●
isosteric substitution C(2) with N keeps activity (⇒2-azafenothiazines)
●in thioxanthenes, compounds with Z-configuration on double bond going out from C(9) have
higher activity than E-isomeres
4. modification of amino group of side chain
●tertiary amines (pKa
8-10) have maximumum activity
●methyls on nitrogen lead to higher activity than longer alkyls; receptor is long and narrow
which is shown by tolerance of phenyl in pos. 2 of the chain
●amino group can be part of a ring; pyrrolidine, piperidine and morpholine belong to useful
cyclic substituents; compounds with piperazine are the most active ones
Mechanism of action of tricyclic antipsychotics
●reversible block of D2
-subtype of dopamine receptor
●evidence of relationship between antipsychotic antagonism against
dopamine agonist apomorphine (displacement of apomorphine from this
receptor) and dopamine accumulation in brain
N CH3
OH
OH
NH2
OH
OH
apomorphine dopamine
Unwanted effects of phenothiazines and thioxanthenes
●Parkinsonian = extrapyramidal syndrome – caused by relative excess of acetylcholine in
CNS over dopamine
●cardiovacular system: dysrythmias of type of Torsade de pointes (TdP; „bundle of spikes“) begins
with QT-interval elongation on ECG due to K+
-channels block – can lead to cardiac
arrest and sudden death (mostly thioridazine)
●„amplified“ vision (lights and colours more intensive, objects bigger)
AP = action potential
IKr
= stream through
K+
channel
„Typical“ neuroleptics: butyrophenones a diphnylbutylpiperidines
Origin of butyrophenones
N
O
CH3
O
CH3
N
O
O
CH3
O
N
OH
O
F
Cl
N
O
O
CH3
O
pethidine
opioid analgesic
propiophenone
analogue of pethidine
● 200x highest
analgesic activity
butyrophenonone
analogue of
pethidine
●analg. activity
comparable to
pethidine, other
activities similar to
chlorpromazine
haloperidol
●prototype = lead
compound of
butyrophenone
antipsychotics
●10x more active
than
chlorpromazine
Butyrophenones
F
O
N
R
1
R
2
R1
R2
INN LP
OH CH3 melperone Buronil
OH haloperidol Haloperidol Richter
OH bromperidol
OH trifluorperidol
pipamperone
H benperidol
Cl
Br
F
F
F
O
NH2
NH
N
O
N
Diphenylbutylpiperidines
N
H
N
O
N
F
F
N
N
H
O
N
F
F
N
F
F
OH
Cl
F
F
F
fluspirilen pimozid penfluridol
Butyrophenones and diphenylbutylpiperidines
Usage:
●treatment of schizophrenia
●neuroleptanalgesia (antipsychotic + opioid analgesic instead
genaral anaesthesia)
Unwanted effect:
●similar to phenothiazines a thixanthenes but no
extrapyramide syndrom
„Atypical“ neuroleptics
●influence serotoninergic system in addition to the dopaminergic one
Tricyclic compounds*
Orthocondensed diazepines
*2251 preparatons authorized in CZ (ATC N05AH)!
N
H
N
Cl
N
N
CH3
8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b
,e][1,4]diazepine
N
H
N
S
CH3
N
N
CH3
2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno
[2,3-b][1,5]benzodiazepine
clozapine
Closapin Desitin®
, Leponex®
olanzapine
Zalasta®
, Zyprexa®
...
Tricyclic compounds
Orthokondensed thiazepines
S
N
N
N
O
OH
S
N
Cl
N
N
CH3
quetiapine
Derin®
, Uxippra®
...clothiapine
Mechanism of action of tricyklic atyp. neuroleptics:
●serotonine antagonists on 5-HT2A/2C
receptor subtype
●strong afinity to dopaminergic receptors but weak to D2
subtype
Unwanted effects:
●agranulocytosis
●cardiovascular system: orthostatic hypotension, TdP dysrhytmias
Indol derivatives
Cl
N
F
N
N
N
H
O
S
N N
N
N
H
O
Cl
sertindole
●5-HT2
and D2
-rp. antagonist
Serdolect®
ziprasidone
●D2
-antagonist
●extrapyramidal syndrome occurs but less
than in „typical“ antipsychotics
Zeldox®
, Zypsila®
...
O N
N
N
N
F
CH3
O
R
Benzoisoxazole derivatives
R = H risperidone Ridoner®
, Rigenin®
...
R = OH paliperidone Invega®
●selectively block D2
and 5-HT2
receptors
●inhibit both positive and negative syndroms
●
AE & toxicity: somnolence, ECG changes, altered perception
Benzamide derivatives
S
O
O
NH2
OCH3
NH
N
CH3
O
H
S
O
O
NH2
OCH3
NH
NCH3
CH3
O
S
O
O
OCH3
NH
N
CH3
O
H
NH2
CH3
R,S-(±): sulpiride
Dogmatil®
, Sulpirol®
...
●selective antagonist of D2
-receptor
●in lower doses antidepressant –
inhibit presynaptic D2
-receptors, in
higher doses postsynaptic ones ⇒
antipsychotic
S-(-): levosulpiride
tiapride
Tiapra®
, Tiapridal®
...
amisulpride
Amilia®
, Deniban®
...