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. Author manuscript; available in PMC: 2014 Jul 11.
Published in final edited form as: J Med Chem. 2013 Jun 20;56(13):10.1021/jm4005219. doi: 10.1021/jm4005219

Table 1.

Antinociception and 24 hour tolerancea evaluation after i.c.v. and i.t. administration of compounds 1-5 and 9-10 in ICR-CD1 mice

Cmpd I.C.V. I.T. Ratio
i.c.v./i.t.
ED50
(95% C.I.)
pmol/mouse		 24hr tolerance ED50
(95% C.I.)
pmol/mouse		 24hr tolerance
1 1219
(859- 1730)		 Day 1: 64.27 ± 6.55
Day 2: 33.85 ± 11.38
Tolerance		 559 (372-
840)		 Day 1: 73.55 ± 10.93
Day 2: 66.01 ± 6.81
No Tolerance		 2.18
2 523
(223-1228)		 Day 1: 77.72 ± 9.78
Day 2: 63.70 ± 16.48
No Tolerance		 27
(13-54)		 Day 1: 81.72 ± 9.48
Day 2: 73.41 ± 11.49
No Tolerance		 19.48
3 55
(37-82)		 Day 1: 83.47 ± 11.59
Day 2: 66.99 ± 9.55
No Tolerance		 42
(31-58)		 Day 1: 98.33 ± 1.79
Day 2: 72.5 ± 11.22
No Tolerance		 1.31
4 189
(132-270)		 Day 1: 95.43 ± 2.93
Day 2: 86.33 ± 7.88
No Tolerance		 19
(11-34)		 Day 1: 78.51 ± 10.44
Day 2: 79.58 ± 9.82
No Tolerance		 9.86
5 9
(6- 12)		 Day 1b: 89.75 ± 10.95
Day 3: 72.81 ± 12.69
No Tolerance		 5
(3- 8)		 Day 1: 92.20 ± 8.34
Day 2: 87.91 ± 6.76
No Tolerance		 1.8
9 108
(83 - 141)		 Day 1: 82.15 ± 9.67
Day 2: 24.14 ± 11.92
Tolerance		 106
(41 - 273)		 Day 1: 75.98 ± 12.73
Day 2: 39.54 ± 14.28
Tolerance		 1.01
10 NSc NAd NS NA
9+10 e 78
(55-110)		 Day 1: 68.84 ± 11.94
Day 2: 43.92 ± 15.20
No Tolerance		 130
(97-173)		 Day 1: 78.00 ± 11.62
Day 2: 74.83 ± 8.45
No Tolerance		 0.60
a

24 hour tolerance was calculated using the highest dose of the dose-response curve on day 1 and repeated on day 2. If there was no significant difference between the two days the animals were said to be not tolerant. Compounds 9+10 (equimolar dose), 1-5 were administered at 2500, 250, 1000 and 125 pmol per mouse.

b

As there was 47% antinociception 24 hours after the initial 15 pmol/mouse (i.c.v.) dose, a 24 hour tolerance test could not be completed. However, after 48 hours the antinociception had returned to baseline and, at this time tolerance was measured by injection of a subsequent 15 pmol/mouse.

c

NS: not significant; compound 10 did not show any antinociceptive activity (only 20-30%) when given at 250 or 2500 pmol per mouse.

d

Not applicable.

e

Doses were based on a 1:1 mixture of compounds 9+10.