TABLE V Esiiation
Yo.
1 2 3 4
1
G
7 8
9 10
CXS stimulants injected in solii 12 log (1/Ll)jo) = 0.290 log P 2.480 log (1,'LDjo) = -0.288 (log E')' 0.902 log P I2
+
+
+ + + +
= =
0.423 0,28d
0 . 688 0.942
0.392 0.193
injected in ~ o l i i 16 0.543 16 0.686
0.470 0.423
1" 12
+
CSS stimulants and depressants log (l/LDja) = 0.323 log P 2.309 log i l !LD,jo) = -0.236 (log P)? 0.829 log P 2.236 log (1,'LDho) = 0.237 log P 0.401 p 0.415 log (1jLDSo) = -0.262 (log P)' 0.792 log P 0.420 p 0.197
+
0.564 0.849
+
2.411 log (1 'LDjo) = 0.202 log P 0.303 p 0.980 log (1jLl)jo) = -0.291 (log P ) ? 0.810 log P 0.31.5 p 0.862
log (l,/LDjo) log (l,/LDso)
,sc
n"
+
+
+ + + +
+
16 16
0 752 0,882
0.383 0.283
CNS stimiilaiits and depressants ( R , in BAW) 12 0,305 0.506 (--Rn,) 2.231 1.086 (-I?") 0.579 p - 0.969 IS 0,877
0,487 0.259
+ +
Depressants ( R , in BAW) G 0.530 0.291 11 log (1,'LDjo) = 0.821 ( - - E m ) 1.247 12 log (1/'LJljo) = 0.897 (--I?">) 2.472 /A - 8.808 G 0 921 0,23,5 , h r = the correlation coefficieiit. c s = $taiidard deviation. n = liiiniber of data points used ill the an ed h>- setting [dilog 1 'c)] '[d(log P)l = 0. log P value for m a l activity. This can he o
Log Pad (rJa'?;, ronfidence interval)
1,369 (1.20-2.59 ) 1,406 (1.14-1.831
1.775
1.312 (1.16-2.51)
+ +
(1
tant role Tliii may be due t o the anchoring of thc drug molecule onto the receptor sites by dipole-dipolc interactions or b j other ti-pe of electrostatic force.; Acknowledgments.-The author\ TI ish to thatill tlic Computer Science Laboratorie. of this University for making the computrr facilitie- available for tlic 1P-
Log Po is the ideal
gressioii alia1 . 11. H. H. 13 especially thankful for tmcc of the R . 31. arid ,J. L. Converse the financial l'und Fcllou .hip: aiid to Awxiate Dean Ednard S Brady foi rnaliing thc fellon ship available. This investigation TI a i wppurted in part by General Research Support Grant 1 SO1 RR-03'702-01, from the General Research Support Branch, Division of Research Facilitiw and Resources, Sationnl Institutes of Health.
Potential Nonequilibrium Analgetic Receptor Inactivators. Synthesis and Biological Activities of N-A4cylanileridines'
P.S.PORTOGHESE," Y.G. TELANG, Dcpart nient of Jf etlzcznal Chenustry, College of Pharmacy, Cnivcrsztij of Minnesota, .llznneapolts, Jfinnesota 56455
A. E.
T A K E X O K I , .%SI)ci.
HATASHI
Uppa?tmcnt of Pharmacology, College of .Ifetlical SczmcLs, Cnzwrszty of diznnesota, Ji'tnneapolis, dfannesota 65465 I40a 8 7 . 1 (5.6-8.9) 9 23.0 (14.8-35.7) 10 18.0 (11.4-28.4) Morphine sulfate 5 . 5 (3.67-8.25) a 80-90% of the animals died within 24 hr after a dose of 40 mg/kg. There was no analgetic activity noted with 20 mg/kg of 7 and only lOy0 of the animals exhibited analgesia with 20 mg/kg of 6.
were employed as standards. Most compounds caused various degrees of CNS stimulation within 5 min after administration followed by sedation in about 1 hr. All compounds produced the Straub tail phenomenon. Severe depression was noted particularly with 2, 6, and 7; death appeared t o be due to respiratory failure. I n fact, the analgetic activity of 6 and 7 could not be assessed due to toxicity. The analgetic activities of 1, 3, and 8 were comparable with that of morphine, while the other compounds tested were 4 t o 8 times less active than morphine. I n all cases where EDso’swere determined, the compounds possessed a very quick onset of action, and the maximum analgetic activity was observed within 20 min after the ip injections. The duration of action was between 60 and 120 min. I n order to determine whether the alkylating agents were capable of blocking analgetic activity, mice were treated with these agents at doses which normally pro-
146 Journal of iVledicina1 Chemistry, 1971, Vol. 14, X o . 2
TICLASG, TAKEMORI, AND
PORTOGHESE,
H.~YAsH[
TABLE I1 PRETREATMENT STUDIES P -ertam t enatCompd
None 2 3 None 2 3 None 5 4 None 3 Kone
40 40 40 40
'0 of animals
Test-------
7 -
Dose, mdkg
Compd
9 Y i
110 XIS
Dose, mg/kg
10 10 10 10 10 10 40 40 40
shoning analgesia
Total analgesia," min-sec m i: S.E.
Increase in reaction' time, sec m & S.E.
15.1 i 2 . 5
90
762.7 i 136.6 c
c
C
1203.7 i 162.4 843 i 173.5
15.9 zt 2 . 0 14.4 i 2 . 3
90 90
c
C
c
w
1131.0 i 22.0 13.6 i 2.7 883.2 1. 116.7 lS.4 i 1 . 6 10 100 746.6 i 171.4 10.6 i 2 . 5 d 50 10 60 775.4 i 201.0 14.3 3 1 . 3 100 cj 0 10 711.0 i 133.5 13.2 i 2 . 1 110 11 40 -~ . 1.7d 309.0 Z!C 9G.Sd .I.? i 40 31s 11 30 404.3 =t86.7 i 2.4 10.7 9 . 0i '30 636.2 i 166.0 12.6 ZlZ 3 . 1 9 50 00 1 20 11.1 i 2 . 4 353.0 i 95.0 Xone 9 30 YO 9.4 i2.8 435.3 i 128.6 6 20 9 50 60 The analgetic effect of the pretreatment drugs had disappeared by 2 hr. a Animals vere pretreated ip 2 hr before the test compound. Meail i S.E. of 10 mice. c All animals died within 2 hr after the test doses. dValues significantly different (I'
