作用神经系统的药物

cis > trans
Chlorprothixene Thiothixene Flupenthixol Zuclopenthixol
R
X
N(CH3)2
N
N CH3
Cl SO2N(CH3)2
N
N CH2CH2OH
CF3
N
N CH2CH2OH
Cl
Butyrophenones
O
F
C(CH2)3 N
R1
Haloperidol
OH
Bromoperidol
OH
Trifluperidol
OH
Benperidol
H
Timiperone Pipamperone
H CONH2
R1
F
R2
O C(CH2)3 N
O NH
N
R2
Cl
Spiperone
t1/2=21h, EPS~80%,
Br CF3
H
N
O
NH
1st generation: barbiturates
O
N NH CH3 2nd generation: Benzodiazepines
1960s
Cl
N+
O-
Chlordiazepoxide
O
N
N
N
Cl
N O
H3C N
N O
Zopiclone
H3C N CH3
O H3C
N N
3rd generations: Pyrrolidones & Imidazo Pyridines
N
O 4, 5
R3
N
O
R1
R2
R1 R2 R3
R4
CH3 H Cl
H
H F Br
H
H Cl Cl
H
CH3 Cl Cl
H
H F Cl CH2CH2OH
Names
Oxazolam
Haloxazolam
Cloxazolam
Mexazolam
Flutazolam
H3C
N
N SN
R
N
Cl
R C2H5
1990s,
CH3
Zolpidem t1/2=2.5h
BZ1/2
�
GABA, 40%
GABAA GABAB GABAC GABACl-
Cl-
Cl-
�
GABAAa
�
GABA
Cl-
�
GABAA agonist
�
BZ1nonsedative),
BZ2(
Chlordiazepo xide Librium Cl 1960s
�
Mosapramine
6
7
Promethazine 8 9
first
phenothiazine
Chlorpromazine
Acetylpromazine
Triflupromazine
Perphenazine
Fluphenazine
1.
5
Swenku.baidu.com
4
3 SAR
S
10
2
N
1
CH2CHN(CH3)2
R3
Cl
CH3
H
CH3
H
CH3
H
H
--
O
F
N
S
O
N N
CH2CH2 N CH3
Risperidone
OH
N
N
O
N
5HT2/DA2
quetiapine
N Cl
Mosapramine
N N
Clozapine
CH3 N
N N
N
S CH3
H
O
N
H
Olanzapine
DopamineDA1~5DA2cAMP
O
2
B3
N4
5
3B
1'
B
6'
2'
C
5'
3'
1N
4'
C
2 ClFBrNO2CF3H
2' 3'4'
2
3 4, 5 5
1, 24, 5
CH3
N
N+ CH3SO4-
O
O
Cl
(CH3)2SO4 Cl
Fe, HCl Cl
CH3C6H5
C2H5OH
ClCH2COCl Cl C6H12
CH3 O N
OH N
O
N
O
N
O
CH3
F
N
O
CH3
Flumazenil
N
OH
Diazepam 45 13
GABAA
O
N
N
N
Cl
N* O
H3C N
N O
H3C N CH3
O
H3C N CH3 N
Zopiclone � GABAA
�
� GABAA-Cl-
� S-zopiclone,
HO
S
N
Cl
(CH2)3N(CH3)2
S
N
Cl
CH3 (CH2)3N
H CH3 (CH2)3N OH
CH3O
S
HO2SO
S
N
Cl
N
Cl
(CH2)3NH2
�
�
�
S H2O
h
N
Cl
S
+ HCl
N
OH
R
R
h
H2O
S
N R
S, N
+ Cl
Thioxanthenes
S
X CHCH2CH2R
2Z cis-isomerE trans-isomer
OH
H
Cl
OH
Cl
Cl
O
O
O
O
O
CH2CF3
H
F
Cl
S
R1
N
N N
CH3 N N
CH N
O
N N
N CH3
Cl
N
Cl
N
O2N
N
F
Cl
R2
Midazolam
Loprazolam
1, 2
1, 2
R1
R2
Names
H
H Estazolam
CH3
H Alprazolam
CH3
Cl
Triazolam
R4
N O
N H
N
S
N H
N
Butyrophenones
N CH3
O
O
CH3
F
O C CH2 CH2 CH2 N
R1 X
R2
4
Diphenylbutylpiperidines
R1
R2
R1
F
CH(CH2)3 N
N
R2
HO
Pimozide
N
H
CF3
F OH
O
Cl Penfluridol
Dibenzodiazepines and Dibenzoxazepines
Clozapine 1966
FDA
1990EPS
R2
8
Clozapine Clothiapine
Loxapine Amoxapine
R3 N
N N
X 5
X NH S O O
R1 2
R1 H Cl Cl Cl
R2
N NHCH3
N O
SAR
Cl
CH3 O N
N
Diazepam Valium Oxazepam,
R1
R2
R3
R4
X
Names
R4
H
H
H
H
(CH2)2N(C2H5)2
H
H
NO2
O
Cl
NO2
O
F
Cl
O
A
R4 7
R1 X
CH3
N 1
CH2
B 3 R2
H
5N R3
CH3
C
H
H
F
Cl
H
F
Cl
OH
H
Cl
CH3
N
R2
CH2CH2CH2R1
R1 N(CH3)2
R2
Cl
1
+++
++
N(CH3)2
COCH3
<1
N(CH3)2
CF3
4
++
+++
N
N CH2CH2OH
Cl
10
++
+++
N
N CH2CH2OH CF3
50
+
+
Trifluoperazine Thiethylperazine
Thioridazine
94 � �
1. Antipsychotic drugs Antischizophrenic drugs
2. Antianxiety drugs 3. Antidepressant drugs 4. Antimanic drugs
Antipsychotic drugs Antischizophrenic drugs
� Sedative-hypnotics drugs Benzodiazepines GABAAnon-benzodiazepine GABAA agonist
� antipsychotic drugs classical antipsychotic drugs atypical antipsychotic drugs
Zolpidem � GABAA< � BZR1>BZR2 � t1/2=2.5h
N
N
N
N
H3C
O
N
H3C
Zaleplon � BZR1 � logP=1.23
� t1/2 =1~7h � F=30%
� Sedative-hypnotics drugs Benzodiazepines GABAAnon-benzodiazepine GABAA agonist
NH
F
CH(CH2)3 N
N
F
Fluspirilene
Benzamides D2
CONHCH2 OCH3
N C2H5
H2NO2S
CH3SO2
CONH(CH2)2N(C2H5)2
OCH3
Sulpiride
Tiapride
CH3HN Cl
OCH3 CONH
CH3 N CH2
1970s,
Benzamides
6.
Dibenzodiazepines and
Dibenzoxazepines
7.
Hydroindolones
II. Atypical antipsychotic drugs (less EPS)
�
clozapine Olanzapine Quetiapine
�
Risperidone
--DA
-
-
5-HT21-7-DA
S
F
N
R3
CH2CH2CH2NR1R2
S
F X
O C(CH2)3 N
CH(CH2)3 N
R1 R2
H2NO2S R1 R2
CONHCH2 OCH3
N C2H5
R3 N
CHCH2CH2NR1R2
O
O
N CH2
F CH2CH3
N CH3
N
N
R2
R1
X
� Sedative-hypnotics drugs Benzodiazepines GABAAnon-benzodiazepine GABAA agonist
� antidepressant drugs � antianxiety drugs/ antimanic drugs � anti-Parkinson's Disease Drugs � Anti-Alzheimer's Disease Drugs
Sedative-hypnotics
O H3C
2
CF3 >
4
Cl > COCH3 > H > OH
3
2
8
10
2
9
N
1
R2
CH2CH2CH2R1
-C=
3 ,
X
CH3 N
HR
C
N
N CH2 CH2
S
A
B
C
ABC
B > C > A
B
R,>
CN-S
�
�
2
�
2
A
OO S
N
Cl
S
N
Cl
H
O
O
S
HO
S
N
Cl
N
Cl
S
N
Cl
CH2CH2COOH
Pipotiazine
Mesoridazine
R1
N
N CH3
N
N CH3
R2 CF3 SC2H5
13
+
+
+
+
CH3
N
SCH3
�-1
+++
+
N
CH2CH2OH SO2N(CH3)2
CH3 N
SOCH3
EPS:
-O-, -CH2-, CH=CH-, -CH2CH2-
6
5
S
7
21, 3, 4
I. Classical antipsychotic drugs (Extra-Pyramidal side effects)
�
Phenothiazines
�
Thioxanthenes
�
Butyrophenones
Dopamine
�
Diphenylbutylpiperidines
5.
CH3 N COCH2Cl
O C
(CH2)6N4 HCl Cl CH3OH
N
N
N
N
Diazepam
CH3
N
O
N
NHCH3 O
C
Cl
CH3
O N
H+
Cl
N
H+
OH-
Cl
CH3 NH COOH
N
Cl CH3 O NC
H2N CO
CH3 NH
O C
OH
+ H2NCH2COOH
Cl
Cl
H
N
O
NH HO C
Br
Names Etizolam Brotizolam
R1 X N
R4 O N
R2
R4
N R3
9 N1 2
R3
8
N
O
R1
A B3
CH3 N
7 6
5 N4
R2
1'
N
Cl
N
H3C N
6'
2'
C
5'
3'
4'
R1 N N
N
F
N
SN
R
Cl
N
N
R2
Cl
A
7
NO2CF3 BrCl 689
9
8
A
7 6
N1
Psychotherapeutic Drugs
History � 20 � 1938
� 1928ACh � 19481970FDA � 1952 � 1950 � 1954FDA � 1954"""" � 1958 � 1960 � 1963 � 1968Carlson5-2000Nobel1987
� antipsychotic drugs classical antipsychotic drugs atypical antipsychotic drugs
� antidepressant drugs � antianxiety drugs/ antimanic drugs � anti-Parkinson's Disease Drugs � Anti-Alzheimer's Disease Drugs
Nemonapride
OCH3
C2H5
Br
N CONHCH2
Sulpiride D1F>90%, t1/2=4~7h
OCH3
Remoxipride
Hydroindolones
O
O
N CH2
CH2CH3
N H
CH3
Molindone
CH3O
CH2CH2 N
N
CH3O
N H
CH3
Oxypertine
� antipsychotic drugs classical antipsychotic drugs atypical antipsychotic drugs
� antidepressant drugs � antianxiety drugs/ antimanic drugs � anti-Parkinson's Disease Drugs � Anti-Alzheimer's Disease Drugs