1 186 186 (1) - 192 (2) (ISAintrinsic sympathomimetic activity) 199 (3) ( MSAmembrane stabilizing activity) 2 (4) 21 (5) 212 (6) 216 (7) 219 (8) 224 (9) (ASL-8123) - 229 (1) d-esl l-esl - 231 2 235 235 (1) ESL 237 (2) (ASL-8123) 24 (3) d-esl l-esl 243
ESL ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O JAN( ) JAN( )esmolol hydrochloride r-inn( )esmolol O H OH H N CH 3 CH 3 HCl d-esl ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O O OH H N CH 3 CH 3 HCl ESL d l-esl ()-methyl 3-{4-[2-hydroxy-3-(isopropylamino)pro poxy]phenyl} propanoate monohydrochloride H 3 C O O O OH H N CH 3 CH 3 HCl ESL l ASL-8123 3-{4-[2-hydroxy-3-(isopropylamino) propoxy]phenyl}propanoic acid monohydrochloride HO O O OH H N CH 3 CH 3 HCl
( ) APA AP5 AP1 EC5 EC8 EC95 HPLC i.v. IC5 ISA Kd Ki LD5 LOQ LV dp/dt MAC MSA NE NLA Post EC5 Pre EC5 QTc RMP RPP SNP TOF TTC Vmax WB-411 5 1 5% 8% 95% 5 (intrinsic sympathomimetic activity) 5 (minimal alveolar concentration) (membrane stabilized action) (Neurolept analgesia) 5% 5% QT (QT / ) (Rate Pressure Product) 2-([2,6- ]-1,4-
31-7 M pa2 ( 1)6.82 (in vitro- ) 31-5 M( ) 11-5 M ( 2)5.18 ( 2)4.79 11-4 M( 1/ 2 / 44.67 ) / 18.43 (in vitro- ) 5.651-8 M 11-2 M 313 (in vivo) g/kg/ (i.v. ) 131 g/kg/ (i.v. ) 11-8 M 11-3 M 11-6 M 11-8 M 11-3 M 31-9 M (ISA) 11-3 M Ki (nm) 1 5.171 3 2 11.51 3 1 218.561 3 2 127.151 3 1/ 2 2.23 1 2 pa2 7.19 3 7.46 (5 ).19 g/ml 1) 5 1 g/kg/ 11.3 3 g/kg/ 11.8 1 g/kg/ 11.6 4 11-4 M 11-4 M 11-7 M 31-8 M1 1-5 M(31-6 M 12.4) 5 ( 11 ( )5 6 MSA) 5 L( ).313 mg/kg 7 (i.v. ) PR 3mg/kg.3 3mg/kg ESL ( 1 ).131.114 g/ml(.3mg/kg).26.558 g/ml(1mg/kg)1.342.5 g/ml(3 mg/kg) 15 ISA (intrinsic sympathomimetic activity) MSA (membrane stabilizing activity) 1) 186
15.313 mg/kg (i.v. ) 1 mg/kg (i.v. ) NLA 1 mg/kg (i.v. ) 12.52 g/kg/ (i.v. ) 31 g/kg (i.v. ) 11 g/kg (i.v. ).111 g/kg/ (i.v. ).313 mg/kg (i.v. 18 ) 8.3mg/kg 1mg/kg PR QTc 3mg/kg ( 1 ).318.539 g/ml(.3mg/kg)1.2.63 g/ml (1mg/kg)4.631.4 g/ml(3mg/kg) 3 PR ( 1 ).366.766 g/ml PR QT ( 1 ).7711.1 g/ml 15 (5)35.6 g/kg/ (5)249 g/kg 4 9 1 g/kg 1 1 g/kg/ 1 mg/kg18.8 3 mg/kg12.4 ( 42.1) 11 12.1.31mg/kg (i.v. ) 187
18 d 31-6 M 31-6 M 31-6 M 31-5 M 31-6 M 254 g/kg/ (i.v. ) ESL.5 1 13 MAC ESL EC95 3 14 16 EC95 1 d EC95 3 17 d ESL SNP (ASL 8123) l ESL 31 - M (in vitro) 11-2 M (in vivo).225.6 mg/kg/ (i.v. ) pa2 3.73 (5 )293 g/ml 31-7 M (in vitro) 31-5 M ( ) (in vitro- ) 11-5 M 11-4 M ( ) 5.651-8 M 11-2 M pa2 ( )desl6.7lesl 7.36ESL7.12 pa2 ( )lesl5.53esl5.41 desl Ki (nm) 1 57.851 3 2 1.561 3 1 22.741 3 2 149.621 3 lesl Ki (nm) 1 3.131 3 2 5.831 3 1 95.761 3 2 157.321 3 1/ 2 desl=1.74lesl=1.86 19 2 188
ESL in vitro in vivo 2 ESL 3 ESL ESL ESL ESL ASL8123 ESL desllesl pa2 1/ 2 ESL 1 1 (ESL 44.7 12.6.29)ESL Ki ESL Ki 2/Ki 1 1 (ESL 2.23 1.7.37)ESL 1 In vivo ESL pa2 7.19.3 7.46.1 ESL ESL 6 ESL 11-6 M 11-7 M ESL 11-4 M ESL (11-7 M11-6 M) 189
ESL ISA 31-8 11-5 M ESL MSA 5.2 MSA ESL.31 3mg/kg.3mg/kg 3mg/kg PR ESL.3mg/kg 1mg/kg 3mg/kg PR QTc ESL 1mg/kg PR NLA ESL 1mg/kg PR QT ESL 3mg/kg 1 3mg/kg 3 NLA 1mg/kg 1 3 ESL ESL 5 35.64.5 g/kg/ 249 g/kg 1 1 g/kg 1 1 g/kg/ ESL 1 3mg/kg ( ) 18.87.4 12.43.2 (42.15.9) ESL rate pressure product ESL 19
ESL ESL.5 1 MAC ESL (4) ( NLA) ESL EC95 1 d EC95 3 ESL ESL ESL ESL SNP ASL8123 pa2 3.73.7(ESL 6.82) ASL8123 5 29365 g/ml(esl.19.4 g/ml) ASL8123 ESL In vitro desl lesl pa2 6.7 7.36 desl lesl 1 (Ki ) 57.85 1 3 3.13 1 3 nm desl lesl in vivo 1mg/kg desl 72 / lesl 87 / 191
ESL ( ) ( 1 WB411( 1 ) ( 2 ) in vitro in vivo (Hartley 1 6 ) ESL 31-7 31-5 M 11-5 11-4 M 11-5 11-4 M 11-7 11-5 M 31-9 3 1-7 M 11-7 11-6 M 31-9 31-8 M 1 1-6 11-4 M 31-9 31-7 M ( 1) ( 2) pa2 ( EC5 ) 1 ( 1/ 2) ESL - pa2 ( 1) ( 2) ( 2) 6.825.184.79 1- ( 1/ 2) / 44.67 / 18.43.292.92 ESL 1 12.64 328.13 ESL 1 2 - pa2 ESL 1-1 ( 1) ( 2) ( 2) 1 ( 1/ 2) pa2 pa2 pa2 / / slope slope slope (95 ) (95 ) (95 ) 6.82 5.18 4.79 ESL 6.83.99.57 44.67 18.43 (.7.95) (.771.21) (.3.84) 8.4 6.73 (.61.86) 8.85 6.88 (.681.8) 6.93.58 (.27.88) 9.38.88 (.61.15) 5.52 1.1 (.831.37) 8.39 1.19 (1.71.32) antilog( pa2 pa2 ) 12.64 328.13.29 2.92 192
(Wistar ) ( 1- )( 2- ) ( 1-2- ) 23 ( 1- - 45 2 3 ) ESL 11-2 M 3 5.651-8 M 11-2 M( 1-2- ) 1 1-3 M( 1-2- ) 3 5.651-8 M 5.651-9 M 11-3 M( 1-2- ) 11-6 M( 1-2- ) 3 5.651-9 M 5.651-12 M - WB411 11-6 M 3 5.651-12 M (Ki ) Ki 1/Ki 2 ESL 1-2- 1-2- Ki 218.5662.411 3 127.1519.991 3 5.17.291 3 11.5.51 1 3 (nm) 1-2- Ki 1- (Ki 1/ Ki 2)2.23 -.37 ESL 1- - 1.7 1- ESL ESL 1- ( 3) - Ki ESL Ki 2/Ki 1 1- - 1-2- ESL 1- - - Ki (nm) 1-2- 1-2-Ki 2/ Ki 1 5.17.29 11.5.51 ESL 45 (1 3 ) (1 3 ) 1.4.21 1.11.1 45 (1 3 ) (1 3 ) 45 4.3.28 1.47.13 193 218.5662.41 (1 3 ) 14.5313.64 (1 3 ) 8.3.54 (1 3 ) 127.1519.99 (1 3 ) 152.13.3 (1 3 ) 8.151.31 (1 3 ) WB411 5 25.551.6 4 6.74.29 Ki 2/ Ki 1 Ki IC5/(1+[L]/Kd)[L] (M)Kd IC5 5 (M) WB4112-([2,6-Dimethoxyphenoxyethyl]-1,4-benzodioxane Hydrochloride 2.23 1.7.37
(1 5 ) ESL 31 3 g/kg/ 2 13 1 g/kg 2 pa2 ( ED5 ) ESL ESL ( 1) pa2 7.19.3 1 8 6 4 2 ESL 4 µ 2 µ µ.1.1 1 1 1 7.46.1 pa2 7.5.6 7.41.4 ( 4) ESL ESL in vivo 1-1 8 6 4 2 194 1 µ 8 6 1 µ 2 µ µ.1.1 1 1 1 µ ESL µ µ µ.1.1 1 1 1 8 6 4 µ µ µ µ.1.1 1 1 1 µ
pa2( ) Slope( ) 95% 5 7.19.3.99.7.84-1.14 ESL 5 7.46.1.89.21.43-1.35 5 7.5.6 1.16.16.82-1.51 4 7.41.4 1.13.1.9-1.35 (1 56 ).5 g/kg ESL 13 1 g/kg/ 2.4 g/kg/ 18 1 () 1 5 ESL 13 1 g/kg/ 18 5 11.3 11.8 11.6 2.4g/kg/ 18 5 6 ( 2) ESL 1 8 6 4 2 µ µ µ µ 5 1 15 2 25 195
ESL ( ) ESL 11-8 11-3 M 345 ESL (NE.2.4g/mL.1.2g/mL) ESL 11-7 11-4 M 615% 11-3 M 34545 46644 35.2 g/ml NE 37946 256 48 ESL 11-7 M 11-6 M 78%.4g/mL NE 37235 23438 ESL 11-7 M ( 3) ESL 11-7 11-5 M ( 5).1.2 g/ml NE 658 ESL 11-7 M 325 NE 11-6 M ESL ( 4) ESL 11-3 M 1 1-7 11-4 M 615% ESL ISA ESL 11-4 M NE 3 25 ESL ISA ESL 11-4 M - 11-7 11-6 M 1 ESL ( ) - 196
NE NE ESL () ESL () NE NE 197
( ) 3M 1 ESL 11-8 11-3 M 153 (RMP) (APA) (Vmax) 5 1 (AP5 AP1) ESL.2.5g/mL ESL 11-8 11-3 M 153 ESL 11-7 11-6 M (RMP) 11-3 M RMP ESL 11-4 M (APA) (Vmax) 5 1 (AP5AP1) ( 6 5).2.5 g/ml ESL 11-7 M 13 - ESL.2.5 g/ml 11-7 M 1-4 M ESL 1mg/kg 1. g/ml ( 11269 ) 3 1-6 M 1/3 ESL 11-7 11-6 M ESL RMP ESL ISA ESL (M) RMP APA Vmax AP1 AP5 87.43.3 1223.3 578117 3139 18917 1-8 866.5 1217 62187 3384 1949 1-7 931.2 1252 6635 325 19723 1-6 91.5.2 1243 67144 32315 19124 1-5 91.2.3 1243 569147 3813 17821 1-4 84.9.5 1158 134141 33713 13414 1-3 48.8.3 p <.5 p <.5 RPM APA Vmax AP11% AP55% 198
(Hartley 1 47 ) ESL 11-9 11-3 M ISA - ISA - 11-9 11-4 M11-9 1 1-4 M 11-9 11-3 M 11-9 11-4 M 1 ESL 31-8 11-5 M (11-6 M 12.4) 11-5 M 31-5 M 16.5 112.3 ( 7) ESL ISA ISA - ISA 199
12 1 8 6 4 2 1-1 1-9 1-8 1-7 1-6 1-5 1-4 1-3 1-2 12 1 8 6 4 2 1-1 1-9 1-8 1-7 1-6 1-5 1-4 1-3 1-2 12 1 8 6 4 2 1-1 1-9 1-8 1-7 1-6 1-5 1-4 1-3 1-2 12 1 8 6 4 2 1-1 1-9 1-8 1-7 1-6 1-5 1-4 1-3 1-2 12 1 8 6 4 2 1-1 1-9 1-8 1-7 1-6 1-5 1-4 1-3 1-2 p.5 p.1(unpaired t ) (Hartley 1 56 ) (5 L) (5 L) ESL 12.55 1.1.2 1 2 ( ) ESL 5 MSA.2 1. MSA ( 6) ESL MSA ESL (1mg/kg 1. g/ml 11 269 )5, ESL 2
() () 1 5 15 3 ESL /5 /5 /5 1 /5 /5 /5 /6 /6 /6 2.5 /6 /6 /6 /6 /6 /6 /5 5 6/6 5/6 /6 /5 /6 /6 /6 /6 1 6/6 6/6 3/6 /6 /6 /6 /6.1 3/6 /6 /6 /6 /6 /6 /6.2 6/6 6/6 5/6 /6 /6 /6 /6 1 4/6 /6 /6 /6 /6 /6 /6 2 6/6 6/6 3/6 /6 / p.5(fisher ) (1 4 ) ESL.31 3mg/kg (PR QRS QT QTc) ( ) 51536 12 ESL 15153 HPLC ESL ESL ( 8 9) ESL 3mg/kg PR 53 22 ( 1)ESL.33mg/kg ESL 1.3mg/kg.131.114 g/ml 1mg/kg.26.558 g/ml3mg/kg 1.342.5 g/ml 15 (.11 g/ml 11) ESL 3mg/kg 3mg/kg PR.33mg/kg 21
5 4 3 2 1 24 22 2 18 16 3 6 9 12 14 12 1 8 6 12 1 8 6 3 6 9 12 14 3 6 9 12 4 3 6 9 12 (n=4) 1 8 6 4 2-2 -4 15 1 5-5 -1 5 1 15 2 25 3 5 1 15 2 25 3 3 2 1-1 -2 4 2-2 -4 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 22
32 24 16 8-8 1 5-5 -1 5 1 15 2 25 3 2 1-1 2 1-1 -2 5 1 15 2 25 3 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1(dunnett ) 1 1.1 ESL.3mg/kg ESL 1mg/kg ESL 3mg/kg LOQ(.11µg/mL) 5 1 15 ESL LOQ 23
1 4 (1.52.5) ( 73) 6mg/kg 24mg/kg/ ( 73) NLA (.75mg/mL) (.15mg/mL) (1mL/kg).5 1.5mg/kg/.1.3mg/kg/ ( 73) ESL (.31 3mg/kg NLA 1mg/kg) ( ) (PR QRS QT QTc) ESL 21 ESL 12 ESL ( ) 15 ( 14) (931) (1537) (252) ( 13)ESL 1 3mg/kg (3 23) (37 38) 5 ( 14)3mg/kg 1 PR (12) 5 QTc ( 1) ( 15) ESL 1.3mg/kg.318.539 g/ml1mg/kg 1.2.63 g/ml3mg/kg 4.631.4 g/ml 3 ( 24) 16 ESL 1mg/kg 15 ( 16) 15 ( 4)( 17) 3 ( 18) 3 ( 24)( 18) PR 1 ( 13) ( 19) ESL 1.366.766 g/ml 15 ( 24) NLA 2 NLA NLA ESL 1mg/kg 15 ( 17) ( 17) ( 21) ( 26)( 22) PR ( 16) QT ( 16) ( 23) ESL 1.7711.1 24
g/ml 15 ( 24) NLA ESL.3 3mg/kg1mg/kg1mg/kg ESL - ) ESL 31 g/kg/ PR QRS 3 HV AH SH class 1 HV ESL ESL.11. 1.mg/kg 1.mg/kg ) (21 ) 3mg/kg ) ESL 31 g/kg/ LV dp/dtmaxrate pressure products ESL ESL - 25
2 15 1 5 1 8 6 4 2 16 14 12 1 8 3 6 9 12 (n=4) 26 2 1 5-5 -2-1 -15-4 -2 5 1 15 2 25 3 5 1 15 2 25 3 1 2-1 -2-2 -3-4 -4-5 -6 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1(dunnett )
2-2 -4-6 4 2-2 -4 5 1 15 2 25 3 5 1 15 2 25 3 15 1 5-5 -1 6 4 2-2 -4 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1(dunnett ) 2 1-1 -2 2 1-1 -2 5 1 15 2 25 3 2 1-1 -2 1-1 5 1 15 2 25 3-3 5 1 15 2 25 3-2 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1(dunnett ) 27
2 15 1 5 16 12 8 4 18 16 14 12 1 (n=4) 1 2 1-1 -1-2 -2 5 1 15 2 25 3-3 5 1 15 2 25 3 2 4 1 2-1 -2-4 -2-6 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5(student t ) 3 6 9 12 28
2-2 -4-6 4 2-2 -4 5 1 15 2 25 3 5 1 15 2 25 3 25 2 15 1 5-5 6 4 2-2 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1 (Student t ) 2 1-1 5 1 15 2 25 3 2 1 2 1-1 1 5-5 -1 5 1 15 2 25 3-1 5 1 15 2 25 3-15 5 1 15 2 25 3 (n=4) ESL 3 p.5(student t ) 29
2 1-1 -2 2 1-1 -2 16 12 8 1 8 6 4 25 2 15 1 5 5 1 15 2 25 3 5 1 15 2 25 3 3 6 9 12 (n=4) 1-1 -2-3 4 2-2 -4-6 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1 (Student t ) 21
2 1-1 -2-3 5 1 15 2 25 3 2-2 -4 5 1 15 2 25 3 8 6 4 2-2 -4 4 2-2 5 1 15 2 25 3 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1 (Student t ) 3 2 1-1 -2 1-1 5 1 15 2 25 3 3 2 1-1 1 5-5 5 1 15 2 25 3-2 5 1 15 2 25 3-1 5 1 15 2 25 3 (n=4) ESL 3 p.5 p.1 (Student t ) 211
1 1 ESL.3mg/kg ESL 1mg/kg ESL 3mg/kg 1 1 ESL 1mg/kg 1 1 ESL 1mg/kg.1 LOQ(.11µg/mL).1 LOQ(.11µg/mL).1 LOQ(.11µg/mL) 5 1 15 5 1 15 5 1 15 ESL LOQ: ESL (1 35 ).5 g/kg ESL 12.52551 2 g/kg/ 2.25.51 2 4 g/kg/ 6 () 1 5 ESL ( 25)ESL 5 35.64.5 g/kg/ 5 2.7.4 g/kg/ ESL 1/13 212
1 1 8 6 4 2 8 6 4 2 5 1 15 2 1 2 3 4 5 (1 6 ) 5 ESL 313 1 g/kg 127 2 g/kg( 131 3 g/kg) ESL 1 5 () 1 () 5 ESL (19 )5 ESL ESL ESL 3 g/kg 21.45.1 1 g/kg 47.87.4 3 g/kg 68.96.4 1 g/kg 85.2.2 ( ) 1 g/kg 26.22.7 3 g/kg 5.62.7 1 g/kg 78.31.8 3 g/kg 94.3.8 ( 26)ESL 5 249 g/kg 5 48 g/kg ESL 1/5 213
1 8 6 4 2 1 1 1 µ (1) 5 ) (1.55.5g/kg/) 3 ESL 1 1 g/kg 3 3 g/kg 3 3 g/kg ESL.1 1 g/kg/ 2 (2 ) ESL 1 g/kg 1 g/kg/ ( 27) 3 g/kg ( 28) ESL 214
1.2.8.4. 4 3 2 1 µ µ 1.2.8.4. 4 3 2 1 µ µ µ -5 5 1 15 2-5 5 1 15 2 (n=5) p.5 p.1(dunnett ) 1.2.8.4. 4 3 2 1 µ µ 1.2.8.4. 4 3 2 1 µ µ -5 5 1 15 2-5 5 1 15 2 (n=5) p.5 p.1(dunnett ) 215
ESL (1 6 ) 2 cm 3 3 ESL.33mg/kg 2 3mg/kg 5 1 15.25 1. 2,3,5 (TTC) 1cm ( ) ( TTC ) ABC 3 D ESL 6 rate pressure product(rpp) ( 29) ( 7)ESL 1mg/kg 3mg/kg 3mg/kg ( ) 18.87.4 12.43.2 16.34.4 (42.15.9) ( 3) ESL 1 3 mg/kg ESL RPP ) (1 5 ) ESL.5mg/kg/ 2 4 ()24.4.6 ESL 7.52.4 216
(A) 2 16 12 8 (B) 16 12 8 (C) 3 2 1 6 12 18 24 3 36 6 12 18 24 3 36 6 12 18 24 3 36 RPP(rate pressure product) (n6) p.5 p.1(dunnett ) 217
(mg/kg) (ml//g) 6.71.238.61.22.725.253.828.315 ESL.3 1 3 6(5) 6 6(5).916.169 1.35.236.676.186.822.77 1.77.154.571.16.841.81.92.113.845.241.998.83 1.241.186.975.326 3 6 1.93.271 1.7.3 1.76.26 1.141.197 6(5) ESL.3 3.mg/kg 1 1cm 3 ABC D (ABC)/3 ()( / )1 (n6) p.5 p.1(dunnett ) 218
(1 45 ) ESL.3 1mg/kg ( ) 135136.1 g/kg/ 1 ESL.1.3 1mg/kg 1 (ESL )ESL 13513612 7.3 mg/kg 3 / /3 ESL.3mg/kg 12 1 ESL1mg/kg 15 2.3 mg/kg 33 ( 31) ESL.3 1mg/kg 15.3 mg/kg 11 3 ( 31) ( 32A) ( 32C) / ( 32D) ( 32E).1 g/kg/ ( 31) ( 32A) ( 32B) ( 32C) / ( 32D) ( 32E) ESL.11mg/kg / ESL.1 1mg/kg.3 mg/kg / 219
ESL ESL1mg/kg 2 / ESL ESL ESL 2-1- 2- ESL.11mg/kg 22
(A) (B) (C) 2 15 1 5-5 -1-15 1 2 3 4 5 6 1 5-5 5-5 -1 15 1 5-5 -1 µ 1 2 3 4 5 6 2 4 6 8 1 12 14 µ 2 4 6 8 1 12 14 (A)n=4(BC)n=5 p.5 p.1(dunnett test) 221
(A) (B) 4 3 2 1-1 25 2 1 2 3 4 5 6 15 1 5-5 -1 1 5-5 2 4 6 8 1 12 14 2 4 6 8 1 12 14 ().1 g/kg/ p.5(dunnett test) 222
(C) 25 2 15 1 5-5 6 5 1 2 3 4 5 6 4 3 2 1-1 2 4 6 8 1 12 14 (D) 8 6 4 2-2 -4-6 -8 25 2 15 1 5-5 -1-15 -2 1 2 3 4 5 6 2 4 6 8 1 12 14 (E).6.4.2. 3 2 1 -.2 1 2 3 4 5 6-1 2 4 6 8 1 12 14 ().1 g/kg/ p.5 p.1(dunnett test) 223
(Hartley 1 1117 ) 5 (Pre EC5) ESL 31-6 M ( ).5 1. MAC ESL 31-6 M 1 5 (Post EC5) ESL ESL Post/Pre Post/Pre ESL Post/Pre 15.251.11.5 1.MAC Post/Pre 14.991.44 15.541.14 19.451.73 18.582. ( 8) ESL 1 MAC Pre EC5 (M) Post EC5 (M) Post/Pre 17 4.371 ( ) -9 3.63 1-1 6.261-8 4.97 1-9 15.251.11.5 15 1 14.5 15 1 11 4.951-9 3.121-1 4.391-9 3.911-1 4.651-9 4.91-1 4.451-9 6.11-1 224 7.191-8 6.621-9 6.671-8 7.1-9 8.541-8 6.971-9 7.651-8 9.621-9 14.991.44 15.541.14 19.451.73 18.582. Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (Hartley 1 8 ) 5 (Pre EC5) ESL 31-6 M ESL 3 1-6 M ( d )EC95 1 3 1 1 5 (Post EC5) ESL ESL Post/Pre Post/Pre
ESL Post/Pre 14.681.14 EC95 1 3 d Post/Pre 13.54 1.43 16.921.85 12.12.97 11.791.44 ( 9) d EC95 1 Post/Pre Post/Pre ( 1) EC95 1 ( 11) ESL EC95 1 d EC95 1 ESL (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) 8 3.931-9 4.131-1 5.891-8 8.551-9 14.681.14 5.741-6 1.911-5 8 8 4.721-9 7.631-1 3.641-9 5.171-1 5.831-8 5.981-9 5.621-8 5.761-9 13.541.43 16.921.85 d 1.251-6 4.181 8 8 3.791-9 3.281-1 3.291-9 3.811-1 4.511-8 3.791-9 3.751-8 4.331-9 12.12.97 11.791.44 Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (M) Pre EC5 (M) Post EC5 (M) Post/Pre ( ) 8 5.21-9 7.11-1 5.341-8 4.691-9 12.181.76 8 4.741-9 3.221-1 6.361-8 6.151-9 13.32.74 d 1.261-5 8 5.31-9 6.571-1 3.451-8 3.611-9 7.32.72 p.5(dunnett ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 (M) Pre EC5 (M) Post EC5 (M) Post/Pre 8 3.131 ( ) -9 4.541-1 4.741-8 4.791-9 16.682. 2.161-7 8 3.651-9 3.41-1 4.71-8 5.531-9 11.311.15 6.481-7 8 2.51-9 2.381-1 3.471-8 3.81-9 17.521.91 2.161-6 8 2.61-9 4.211-1 3.791-8 5.41-9 15.141.49 Pre EC5(M)ESL 5 Post EC5(M)ESL 5 225
(Hartley 1 3 ) 2.2 2Hz 4 (TOF ) EC8 (6.15 1-6 M) d (1.51-6 M) ESL 31-6 M 31-5 M ESL TOF 1 (T1) 1 T1 d ( EC8 ) ESL 31-6 M 31-5 M ( 12) ESL ESL 1) 2) ESL (M) ESL 31-6 M ESL 31-5 M 6.151-6 3 24.642.38 3.742.85 49.423.1 d 1.51 3 24.641.38 23.931.27 2.491.29 p.1(dunnett ) T1 1 T1 1) Murthy V.S., et. al. : Effects of esmolol on circulatory response to intubation and succinylcholine-induced neuromuscular blockade in man. Anesthesiology, 63, 3A, 1985 2) Szmuk P., et. al. : The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine. Anesth. Analg., 9, 1217-1219, 2 226
(Hartley 1 8 ) 5 (Pre EC5) ESL 31-6 M ( ) ESL 31-6 M 1 5 (Post EC5) ESL ESL Post/Pre Post/Pre 11-5 11-4 M ESL 31-6 M Post/Pre 11.71.15 12.381.19 11-9 11-8 M ESL 31-6 M Post/Pre 13.92.95 17.411.44 ESL ( 13) ESL Ca 1) (M) Pre EC5 (M) Post EC5 (M) Post/Pre 8 3.591 ( ) -9 3.611-1 3.921-8 3.91-9 11.761.7 11-5 11-4 8 8 4.1-9 4.11-1 3.61-9 6.81-1 4.551-8 5.521-9 4.131-8 4.741-9 11.71.15 12.381.19 11-9 11-8 8 8 3.381-9 2.31-1 2.691-9 2.671-1 4.691-8 3.91-9 4.61-8 5.421-9 13.92.95 17.411.44 p.5(dunnett ) Pre EC5(M)ESL 5 Post EC5(M)ESL 5 1) 2.4 (199) 227
(1 1 ).3 (SNP) 6mmHg ESL 6mmHg 254 g/kg/ 6 6mmHg SNP SNP ESL 6mmHg SNP SNP 9.62.7 g/kg/ ESL251 4 g/kg/ SNP 6.91.3 8.41.3 g 4.3.8 g/kg/( ) ESL SNP SNP 3 ( 33)ESL SNP ESL ESL SNP 14 12 1 8 6 4 µ µ µ µ ESL 25 1 4 ( g/kg/) SNP 9.6 ( g/kg/) 2.7 6.9 1.3 2 4 6 8 1 12 14 8.4 1.3 4.3.8 (n1) ( ) p.5 p.1(dunnett ) 228
ESL ASL8123 in vitro in vivo ESL (148) ASL8123 31-5 11-2 M 1 ( 1) ( 1) pa2( EC5 ) ASL8123 31-5 31-3 M 11-2 M 257 / ASL8123 ( 34) pa2 3.73.7 ASL8123 11-2 M ASL8123 ( 1) pa2 3.73.7 ESL pa2 6.82 (192 )ASL8123 ESL 1/1 (Shaffer J.E. et al.: -adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol. J. Cardiovasc. Pharm. 11, 187-192, 1988) 229
(1 6 ).5 g/kg 1 ASL8123.2.4.81.63.26.412.8 25.6mg/kg/ 2 ( 4.12.828612425258 12mg/kg) ASL8123 5 ASL8123 ASL8123 58 12 mg/kg 154 227 / ASL8123 25212 mg/kg ASL8123 12.8 12mg/kg ASL8123 252mg/kg 5 ASL8123 29365 g/ml( 35)(ESL.19.4 g/ml )) ASL8123 ESL 1/1 5 ASL8123 (Shaffer J.E. et al.: -adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol. J. Cardiovasc. Pharm. 11, 187-192, 1988) 23
ESL desllesl d lesl (Hartley 1 56 ) desl lesl ESL 31-7 31-5 M 1 ( 1) 3 desllesl ESL 11-5 11-4 M 1 ( 2) ( 1) ( 2) pa2 ( EC5 ) desllesl ESL ( 36) pa2 6.77.36 7.12 ( 14)lESL ESL ( 37) pa2 5.53 5.41 ( 14) desl 11-4 M pa2 desl lesl ESL 1 desl 2 lesl ESL 2 desl lesl in vivo 1mg/kg desl 72 / lesl 87 / (243 ) ESL d-esl l-esl pa2( ) Slope( ) 95% 6 7.12.8.75.7.49-1. 6 5.41.4.75.6.51-1.7 6 6.7.7.65.9.29-1. 56 1) 1) 1) 6 7.36.5.78.4.56-1. 6 5.53.4.91.7.83-1. 1) 1-4 M 231
1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1-1 M 1-9 M 1-1 M 1-9 M 1 8 6 4 2 1-8 M 1-7 M 1-6 M 1-5 M 1 8 6 4 2 1-8 M 1-7 M 1-6 M 1-5 M 1 8 6 4 2 1-1 M 1-9 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-8 M 1-7 M 1-6 M 1-5 M 1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1-1 M 1-9 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-1 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 232
1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1-9 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1-9 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1 8 6 4 2 1 8 6 4 2 1 8 6 4 2 1-9 M 1-9 M 1-8 M 1-7 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 1-9 M 1-8 M 1-7 M 1-6 M 1-5 M 1-4 M 233
(Wistar ) ( 1 ) ( 2 ) ( 1 2 ) ESLdESL lesl 23 ( 1 45 2 3 ) ESLdESL lesl 11-2 M 3 5.651-8 M WB411 11-6 M 3 5.651-12 M (Ki )193 1 2 Ki desl 57.851.831 3 1.566.1 1 3 lesl 3.13.521 3 5.83.991 3 (nm) desl lesl Ki 1 2 Ki desl lesl 1/ 2 1.74 1.86 1 2 Ki desl lesl 22.7434.531 3 149.6234.951 3 95.769.971 3 157.3219.781 3 (nm) ( 15) 1 2 leslesldesl 1/ 2 ESLlESLdESL 1 2 ESL desl lesl Ki(nM) 1 2 1 2 Ki 2/ Ki 1 45 45 45 5.17.29 (1 3 ) 57.851.83 (1 3 ) 3.13.52 (1 3 ) 11.5.51 (1 3 ) 1.566.1 (1 3 ) 5.83.99 (1 3 ) 218.5662.41 (1 3 ) 22.7434.53 (1 3 ) 95.769.97 (1 3 ) 127.1519.99 (1 3 ) 149.6234.95 (1 3 ) 157.3219.78 (1 3 ) WB411 5 25.551.6 4 6.74.29 Ki 2/ Ki 1 Ki IC5/(1+[L]/Kd)[L] (M)Kd IC5 5 (M) WB4112-([2,6-Dimethoxyphenoxyethyl]-1,4-benzodioxane Hydrochloride 2.23 1.74 1.86 234
ESL ASL8123 desllesl ESL 1mg/kg ESL 11-5 g/ml(31-5 M) 11-4 g/ml(31-4 M) 11-3 g/ml(31-3 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) ESL 11mg/kg 3mg/kg 3mg/kg 1 mg/kg 11-4 g/ml ESL 1mg/mL ASL8123 1mg/kg 6 ASL8123 1mg/kg ASL8123 1 ASL8123 11-3 g/ml 11-4 g/ml 11-5 g/ml ASL8123 1mg/kg ASL8123 3mg/mL ASL8123 11-3 g/ml ESL desllesl 2.52mg/kg 6 desl lesl 11-4 g/ml 11-4 g/ml desl 52mg/kg lesl 2.51mg/kg desl 1mg/kg 15 2mg/kg 1 desl lesl desl lesl 11-4 g/ml 235
ESL desl lesl ASL-8123 1 1-5 g/ml ESL 3 1-7 M31-6 M(11-7 11-6 g/ml192 ) ESL 11 ESLdESL lesl (192 ) leslesld-esl ( 22) l d-esl ESL ASL8123 1mg/kg 11-3 g/ml ASL8123 ESL ESL ESLASL8123dESL lesl 236
16 ESL 11-4 g/ml(31-4 M) 11-3 g/ml(31-3 M) 11-5 g/ml(31-5 M) 1 1-4 g/ml(31-4 M) 11-3 g/ml(3 1-3 M) 11-4 g/ml(3 1-4 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) ESL 13 1mg/kg 3mg/kg PR 3 mg/kg QT QRS QTc 15 11 mg/kg 45 3 mg/kg 1 mg/kg ) ESL 1.258mg/kg 2.51.252.5 4mg/kg ESL 1mg/mL 237
(1 ) (Irwin (6) ) (15) ( (6) ) ( ) (6) ( Writhing ) (6) 238 131 mg/kg 131 mg/kg 131 mg/kg 131 mg/kg 131 mg/kg 131 (6) mg/kg ( ) 131 (1) mg/kg in vitro 11-6 (4) 11-4 g/ml (31-6 3 1-4 M) in vitro 11-5 (6) 11-3 g/ml (31-5 3 1-3 M) in vitro 11-6 (4) 11-4 g/ml (31-6 3 1-4 M) in vitro 11-6 (4) 11-4 g/ml (31-6 3 1-4 M) in vitro 11-6 (6) 11-3 g/ml (31-6 3 1-3 M) 11-5 g/ml(31-5 M) 1 1-4 g/ml(3 1-4 M) 11-3 g/ml(31-3 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M) 11-4 g/ml(31-4 M)
239 (1 ) ( ) (3) 131 mg/kg (3) 131 mg/kg 3mg/kg ( ) (3) 131 mg/kg 3mg/kg PR QT QRS QTc (3) 131 mg/kg 11mg/kg 45 (3) 131 mg/kg 3mg/kg (3) 131 mg/kg 1mg/kg (6) 131 mg/kg (67) 131 mg/kg (56) 131 mg/kg (6) 131 mg/kg (46) 131 mg/kg (56) 131 mg/kg (67) 131 mg/kg (6) in vitro 131 mg/ml 1mg/mL
ASL8123 1mg/kg 5 6 12 6 ASL8123 1mg/kg ASL8123 13 1 11-3 g/ml 11-3 g/ml 11-3 g/ml 11-4 g/ml 11-3 g/ml 11-4 11-3 g/ml 11-5 g/ml 11-3 g/ml ASL8123 1mg/kg 1 15 11-3 g/ml 11-3 g/ml 3mg/mL 24
(1 ) 131 (Irwin (6) ) 13 1mg/kg 1 3mg/kg 1 mg/kg 6 1 11mg/kg (6) 31 mg/kg ( (6) ) ( ) (6) ( Writhing ) (6) (6) (6) ( ) 13 1mg/kg 13 1mg/kg 13 1mg/kg 13 1mg/kg in vitro 11-5 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml in vitro 11-6 (6) 11-3 g/ml in vitro 11-5 (6) 11-3 g/ml 131 1 ( ) 11-3 g/ml 11-3 g/ml 11-3 g/ml 1 1-4 g/ml 11-3 g/ml 11-4 11-3 g/ml 1 1-5 g/ml 1 1-3 g/ml 241
(1 ) 1 3 1 (6) mg/kg 1 3 1 (6) mg/kg 1 3 1 (6) mg/kg 1 3 1 (6) mg/kg in vitro 11-5 (6) 11-3 g/ml 1 3 1 (6) mg/kg 1 3 1 (6) mg/kg in vitro (6) 131 mg/ml 1 mg/kg 1 mg/kg 15 11-3 g/ml 11-3 g/ml 3 mg/ml 242
18 desl 52mg/kg 12mg/kg 5 2mg/kg 2mg/kg 4 12 6 lesl 2.51mg/kg 2.5 1mg/kg 1mg/kg 4 13 6 desl lesl 5 1 desl lesl 1 desl lesl 1 1-4 g/ml 1 1-5 g/ml 1 1-4 g/ml 1 1-4 g/ml desl lesl 1 1-4 g/ml 11-3 g/ml desl 1mg/kg 15 2mg/kg 1 desl lesl desl 52mg/kg (1mg/kg 1 72 / ) lesl 2.51mg/kg (1mg/kg 1 87 / ) lesl desl desl lesl 1mg/mL 243
(1 ) (4) (Irwin ) 1 1-4 g/ml lesl (desl) 512 (lesl) 2.551 mg/kg (6) in vitro 11-6 (4) 11-4 g/ml ( 1) in vitro 11-6 (4) 11-4 g/ml in vitro 11-6 (4) 11-4 g/ml ( 1) in vitro 11-6 (6) 11-3 g/ml ( 3) (desl) (6) 512 (lesl) 2.551 mg/kg in vitro (6) desl 52mg/kg 12mg/kg 5 2mg/kg 2mg/kg 4 12 6 lesl 2.51mg/kg 2.5 1mg/kg 1mg/kg 4 13 6 51 desl lesl1 2.551 mg/ml desl lesl 11-4 g/ml desl lesl 1 1-5 g/ml 1 1-4 g/ml desl lesl desl lesl 11-4 g/ml 1 1-3 g/ml desl 1mg/kg 15 2mg/kg 1 desl desl 1mg/kg 72 /( 1 ) lesl 1mg/kg 87 /( 1 ) 1mg/mL 244