May, 1963
339
SOTES
erties in depressed patients. The final characterization of the psychotropic properties of these compounds must await clinical studies.
compounds possessed profiles of pharmacological activity similar to that of amitriptyline and, therefore, they could be expected to possess antidepressant prop-
TABLE I
/"\
X
Y
Ternperature decrease Composlnd no. 1 2 3 4 5
6 7 8 Y
10 11 12 13 14 1.j 16 17 18 19 20 21 22 23 04 '3 - I
.j
26 27 28 29 30 31 32 J3 31 3 .i 3 li 37 38 39 40
41 4" 4s 41 A i
40 47
--
R
CHz-CHz-
7
Z
H I-I
H
N H H €I H H H 13
H NO
HO Ii " II
H H
11 €I €1 €I H €I H H HP
H
II" Hq
H 11'
II i-
H I1 11'2
H 2-Cl
:i-ci : 3 a 3-C1 H :i-ci9
3-CI :i-C1
:{.TI
LD60 approx. nig./kp. (mice) 120-130 112 f 3 83 f 2 100-450 70-80 60-70 55-65 180-210 80-90 80-90 oo-iin 90-110 115-123 100-110 130- 130 270-920 180-?20 210-2'30 220-270 110-13.5 80-90
1 5..143 115- 1 23 1HO-175 PO-90 75-40 60- 70 115-125 7540 93-1!.5 105-125 70-75 3,5-60 90-100 i.0-90 60-7.3 4 5- ,j,j 00-115 io-00 !,0-110 80-90 90.-100 4,i-0:
911-110 "1-110 117 rt 3 6
O C
mice (*rats) '14 LD50
3 5 3 . .5
..
.. 2 5 4.1 0.84 0.6 4.1 1.6* 2* 2.1" 5.6 2.3* 1.1* 2.1"
..
l.i* 3.2 2.1 1* 2.1* ?.4*
2.3*
0 1.9* 1* 1.5
O*
.* L '
O* 0% O* 2.3*
..
2.3* 4 4.9 7.4
6.9 1.74 7.1 11 2.5*
Run-
MpdriRlES asis ED50 1/1 LDio mg./%q. (mice) (mice) 7 29 f 0 . 7 31 15.5 i 1 19 10 i 0 . 8 3 .i > I O 0 10 19 i 3 .. 1 7 i l 16 8 1 6 . 5 zk 1 2 2 5 i 4 1.1 22 i 1 10.8 1 6 . 5 i 0.3 17.4 13 3 =I= 1 . 2 24 13.5 i 0 . 9 3.8 20.3 i 1 5.4 33 i 1 . 4 0 3 0 i 1 2 2 106 f 9 1 0 . 8 36 i 1 . 8 0 >60 >
21 9.1 14.4 8.1 6 13 19 0 2.1 15 17 4.4 3 .i 25.8
6 3 :3 24 0 0 8 8 15 8
..
.. 2.6 24.6
2.8 1.8
.\lcuhol potentiation
EDso n1g./kg.
(mice)
33 j; 2 10 f 0 . 2 7 . 9 & 0.8 83 =I= 7 7.5 i 1 13 i 2 14 i 1 . 4 22 5 10.5 + 1 11 f 0 . 5 12 f 1 . 4 15 i 1 . 8 17 & 1 . 1 l ? , , j =t 1 . 3 8.5 17 44 f 2 23 i 1 . 8 1 1 0.1 3 2 = n 9 >53 22 i 1 22 i 2 20 1 222 2 7 . 5 i 1 . 4 24 zt 5 ? O f 1 4 27 i 1 . 4 2 1 1 1 3 23 i 1 . 6 12 i 1 . 5 13 zk 0.6 14 i 2 9.8 i 0.9 18 i 3 >l5 34 i R 26 i 3 22 i 6 27 5 17 i 2 . 2 10.5 i 1 13 i 1 . 4 >35 5 i l 21 i 1 0 . 9 =t0 . 2 17 i 2 34 z7 3 21.6 i 2 2: i 2 13 i 4 2 6 i 0.6 16.7 1 3 . 7 ,L 2 >15 15 f 3 37 i 1 >l5 >l5 22 f 1 . 2 17 1 2 20 f 2 . 4 1.5
+
*
+
+
*
19.2 f 1.4 22 1 1 . 7 25 10 . 5 20 5 0 . 8
29 f 1 . 5 >20
5 . 7 f 0.8 1 7 i 2 6 10 i 1 1.7 0.5 11 f 0 . 9 15.8 i 1 . 3
*
a ay
Ataxia etfect approx. approx. ED3 ED50 ITlg./kg rng./kg. (rats) (rats) 30 55 40 11 8 53
..
.. 8 Y 14
.. 16 15 12 8 8 8 6
24 45 23 >YO 45
>40 70 43 50 50 45
.. 18 18
in Ii 20 10 22 13 13 10 23
13 12 24 7 8 22 6 3 10 18 13 10 10
9 18 8 5
7 20
62 90 >110 3 ,j 33 60 63 60 30 30 47 66
-_ .a:>
40 >90 40 26 70
__
i>.,
30
-
.) I
00
Guinea Pig Ileum Antihistamine relative AntiPOAch tency; relative propotency; niethaatropine zine = 100 = 100 0.27 4.5 114 35 9.5 PO 0.03 0.14 1.4 40 7 27 22 31 2 0 3 1 3 33 30 1.6 15 4.5 11 22 0 4 40 0.2 6.9 1 2 6.8 0 09 2.2 2.8 36
..
.. 0.13 10 2.3 6.5 13 40 :3 0
0.6 9.5
34 16
45 50 22
14 8 1.6 8 3
45
19
66 3 13 18 3 0.7
GO
>55
..
0.7
..
SCjH,, = pipsridino. * SC6Y12= 2 msthylpiperidino. c SC5H8 = 1,2,5,6tetrahydropyridino. ?r'zCjHll = 4-methylpiperazino. e SIC,jH,~O= 4-("-h\-drouyetli\-l)~ip.razino. XrC8H,,Oy = 4-(2-acetosyethyl)piperazino. TCrHEO = morpholino. Ii;CI,HjEO* = ~-carbetliouv-~-plienylpipsridino. CeHl2?; = l-rneth~-l-3-piperid,vl. j CjH,,X = 1-methyl-3-pyrrolidyl. IC CeH& = l-methyl-2C,HI,?; = 2-piperid,yI. 7n higher melting point geometric isomer. lower mnlting point geometric isomer. ' PHCL. piperidyl. base. HgSO4. ' oxalate. ' HaPo,. 0
