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1 30mg
2 ...i... iii (1)... 1 (2)... 1 (3)... 1 (4) (1)... 2 (2) (1)... 6 (2)... 8 (3) SIAD (4) V (5) (6) (7) (1) (2) (1) (2) SIAD (3) (4) (5) i
3 (6) ii
4 AD ADP APA APD 30 AUC AVP camp CI C max CPM DDAVP DMF ED 3 GABA PMC ela IC 50 i.p. i.v. Ki p.o. s.c. SD SIAD t 1/2 V max antidiuretic hormone 30% 3, 5 - central pontine myelinolysis [deamino-cys 1, D-Arg 8 ]- 3 50% Sprague-Dawley syndrome of inappropriate secretion of antidiuretic hormone iii
5 JA PC PC-129 M1 5- PC M2 4,5- DM-3109 M3 4,5- DM-3111 M4 5- PC M5 5- PC M6 DM-3105 M7 SF M8 5- PC M9 DM-3112 M10 DM-3118 M11 DM-3119 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C l C 3 C 3 C C iv
6 M12 DM-3120 M13 - DM-3130 C 3 C 3 C 3 M14 DM-3153 M15 DM-3155 M16 DM-3157 M17 C 3 M-3 M18 M-4 M19 M-7 M20 M-8 M21 M v
7 R(+)- R(+)-PC (R)-(+)-PC S(-)- S(-)-PC (S)-(-)-PC R(+)-M1 R(+)-PC (R)-(+)-PC S(-)-M1 S(-)-PC (S)-(-)-PC (4R, 5S)-(+)-M2 (4R, 5S)-(+)-DM-3109 (4S, 5R)-(-)-M2 (4S, 5R)-(-)-DM-3109 (4S, 5S)-(+)-M3 (4S, 5S)-(+)-DM-3111 (4R, 5R)-(-)-M3 (4R, 5R)-(-)-DM-3111 R(+)-M4 R(+)-PC (R)-(+)-PC S(-)-M4 S(-)-PC (S)-(-)-PC R(+)-M5 R(+)-PC (R)-(+)-PC S(-)-M5 S(-)-PC (S)-(-)-PC C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C vi
8 (1) I mozavaptan JA Mozavaptan ydrochloride -(4-{[(5RS)-5-()-2,3,4,5--1-[b]-1-] })-2- -(4-{[(5RS)-5-(dimethylamino)-2,3,4,5-tetrahydro-1-benzo[b]azepin-1-yl]carbonyl} phenyl)-2-methylbenzamide monohydrochloride CAS PC-31260PC-129 C 3 C Cl (2) Cl C 3 C 3 V 2 -V 2 - syndrome of inappropriate secretion of antidiuretic hormonesiad (3) (4) 30 mg
9 in vitro in vivo (1) (a) [ 3 ]- V 2 -Ki 9.42±0.85 nm V 2 -Ki 6.36±1.56 nm V 2 -Ki 5.07±1.42 nm V 2 - V 1a - V 1a - 1/8 1/82 1/23 V 1b -V 1b - V 2 - ela camp V 2 - (b) (c) SIAD SIAD SIAD V 2 - [deamino-cys 1, D-Arg 8 ]-DDAVP 1 ng/h 1, 3 10 mg/kg 10 mg/kg central pontine myelinolysis, CPM
10 2 mg/kg10 mg/kg SIAD (d) V 2 - V 2 -in vitro in vivo V 2 - ela camp V 2 -Brattleboro V 2 - (e) V 1a - IC µm V 1a - 1 mg/kg i.v. 10 µm 70%IC µm 56% Ki 1.44 µm V 2 - Ki 9.42 nm (f) M1M7 7 M1 M2 V 2 - M3M4 M5 V 2 -V 2 - V 2 - M6 M7 V
11 (g) V 2 -S(-)- R(+) S(-)- R(+)- in vivo (2) (a) mg/kg p.o. 300 mg/kg p.o mg/kg p.o. 6/ mg/kg p.o. 1/5 200 mg/kg p.o. 3/5 25 mg/kg p.o. 2/ mg/kg p.o. 4/ mg/kg p.o. γ- (GABA) A GABA B 300 mg/kg p.o. 30 mg/kg p.o.100 mg/kg p.o. 300 mg/kg p.o. 30 mg/kg p.o. 100 mg/kg p.o mg/kg p.o mg/kg C max µg/ml 300 mg/kg p.o.10 mg/kg i.v. 10 mg/kg i.v. 1 µm 10 µm 1 mg/kg i.v mg/kg i.v. PQ ST 10 mg/kg i.v.qrs QT
12 1 µm 30 µm 200 mg/kg p.o. 1 µm 10 µm APA V max APD 30 PQ QRS a Ca 300 mg/kg p.o. 3 mg/kg i.v.10 mg/kg i.v. 30 mg/kg p.o. 100 mg/kg 1000 mg/kg 30 mg/kg 30 mg/kg i.v. (b) M1M7 1 mg/kg i.v.10 mg/kg i.v. M1 M2 10 mg/kg i.v. 0.3 mg/kg i.v. M3 10 mg/kg i.v M4M7 M5 0.3 mg/kg i.v.m4 1 mg/kg i.v.m6 3 mg/kg i.v.m2m3 M7 10 mg/kg i.v.m5 0.3 mg/kg i.v.m4 1 mg/kg i.v. M1 3 mg/kg i.v. M3M6 M7 10 mg/kg i.v. M5 1 mg/kg i.v.m6 3 mg/kg i.v. 10 mg/kg i.v.m7 10 mg/kg i.v. 0.3 mg/kg i.v.m4 M5 1 mg/kg i.v. T 3 mg/kg i.v. ST QRS M5 3 mg/kg i.v. PR QT 10 mg/kg i.v. M3 T PR QT M7 ST T
13 (1) (a) V 1a -V 1b - V 2 -[ 3 ]- [ 3 ]- (i) V 1a -V 1b - V 2 - ela 1,2,3 [ 3 ]- V 2 - V 1a - V 1b Ki V ±0.85 nmv 1a ±22.7 nm V 1a - V V 2-9 V 1a -4 V 1b V 2 -, V 1a -, V 1b -[ 3 ]- ±
14 KinM V ±0.85 (9) 6.36±1.56 (5) 5.07±1.42 (4) 0.89±0.11 (9) 1.19±0.28 (4) 1.21±0.43 (4) V 1a ±22.7 (4) 524±119 (5) 118±11 (4) 0.77±0.21 (4) 1.53±0.31 (5) 1.67±0.56 (4) V 1b - I (4) 1.10±0.44 (4) I10 µm 50% ± (ii) V 2 -V 1a - 4 V 2 - V 1a - Ki 6.36±1.56 nm 524±119 nm V 1a - V (iii) V 2 -V 1a - 5 V 2 - V 1a - Ki 5.07±1.42 nm 118±11 nm V 1a - V (b) camp V 2 - ela camp V nm camp 1 nm camp camp 50IC ±83 nm
15 camp 1nM AVP Log[(M)] V 2 - ela camp V 2 - ela 1 nm10 camp 100% 4 ± (c) V 2 - V 2 - ela camp V 2 - (2) (a) V 2-6 SD 7 8 (i) 1%PMC SD 130 mg/kg mg/kg3100 mg/kg mg/kg mg/kg mg/kg
16 (ml/kg/4hr) (msm/kg) (meq/kg/4hr) (meq/kg/4hr) (meq/kg/4hr) (mg/kg/4hr) * a K Cl * * 0 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg (ml/kg/24hr) (msm/kg) (meq/kg/24hr) (meq/kg/24hr) (meq/kg/24hr) (mg/kg/24hr) a 6 * K Cl mg/kg 3 mg/kg 10 mg/kg 30 mg/kg ±n=8*: p<0.05, : p<0.01 Dunnett
17 a (meq/kg/4hr) (ml/kg/4hr) , 3, 10, 30 mg/kg10, 30, 100, 300 mg/kg 3, 10, 30, 100 mg/kg30, mg/kg ±n= (ii) 330 mg/kg1, 3 mg/kg mg/kg 3 mg/kg 1 3 mg/kg mg/kg p =
18 ml/kg msm/kg ml/kg msm/kg a meq/kg a meq/kg ml/kg/min mg/kg ml/kg/min mg/kg ±n=8: p<0.01 Dunnett , 4.2-2, a (meq/l) * a (meq/l) (ng/ml/hr) (ng/ml/hr) AVP (pg/ml) mg/kg AVP (pg/ml) mg/kg AVP ±n=8*: p<0.05, : p<0.01 Dunnett , 4.4-2, 4.5-1,
19 (iii) mg/kg 6 30 mg/kg 3 mg/kg (b) SD 9 1%PMC 3 10 mg/kg mg/kg mg/kg (ml/kg) * * 0-4 * ## ## (ml/kg) # ## (msm/kg) ## ## (msm/kg) * mg/kg 10 mg/kg ## ## ±n= *: p<0.05, : p<0.01#: p<0.05, ##: p<0.01 Dunnett
20 (c) (3) SIAD SIAD (a) SD V 2 - DDAVP 30 ng/h 1 2 5% SIAD meq/l 30 mg/kg ±2.9 meq/l102.6±3.2 meq/l 80.00±0.16 % 79.18±0.12 % (b) Verbalis 14 SIAD SD DDAVP 1 ng/h 110 meq/l DDAVP mg/kg mg/kg mg/kg 30 meq/l CPM
21 SIAD 1 mg/kg 3 mg/kg 10 mg/kg (meq/l) * ## ## ## DAY SIAD 1%PMC DAY4DDAVP ±6 SIAD 7 1 mg/kg 7 3 mg/kg 7 10 mg/kg 3 4 *: p<0.05, : p<0.01siad ##: p<0.01 SIAD DAY4 Dunnett (ml/day) (msm/kg) (meq/day) SIAD (mg/kg) SIAD (mg/kg) SIAD (mg/kg) SIAD 1%PMC DDAVP ±6 SIAD 7 1 mg/kg 7 3 mg/kg 7 10 mg/kg 3 4 : p<0.01siad Dunnett
22 mg/kg meq/l Appendix 3 (c) b SIAD DDAVP 5 2 mg/kg mg/kg 10 mg/kg mg/kg 10 mg/kg 141.3±0.7 meq/l SIAD SIAD SIAD
23 150 SIAD (meq/l) mg/kg 4 mg/kg 6 mg/kg 8 mg/kg 10 mg/kg ## DAY SIAD 1%PMC DAY4DDAVP ±6 SIAD 7 7 : p<0.01siad ##: p<0.01 SIAD DAY4 t SIAD (msm/kg) (meq/l) (meq/l) (meq/l) (mg/dl) (%) ± ± ± ± ± ± 0.4 SIAD ± 2.3 ## ± 1.2 ## 4.45 ± 0.08 ## 74.8 ± 1.0 ## 0.26 ± 0.02 ## 33.1 ± 0.4 ## ± ± ± ± ± ± 0.6 ±6 SIAD 7 7 : p<0.01siad ##: p<0.01 SIAD t SIAD t
24 ## SIAD (g/kg) ## (%) ## SIAD ±6 SIAD 7 7 : p<0.01siad ##: p<0.01 SIAD t SIAD t (d) SIAD (4) V V 2-15,16 Brattleboro 17,18 V 2 -in vitro in vivo (a) camp V 2 - V 2 - ela camp V µm camp camp (%)1 µm: 96±7 %10 µm: 100±5 % ( n=3) V
25 (b) Brattleboro V 2 - Brattleboro SD 30 mg/kg p.o. d(c 2 ) 5 Tyr(Et)VAVP10 µg/kg s.c. V 2 - DDAVP10 ng/kg s.c. 19 d(c 2 ) 5 Tyr(Et)VAVP Brattleboro V 2 - Brattleboro V ml/kg Brattleboro ml/kg msm/kg msm/kg * µ Brattleboro d(c 2 ) 5 Tyr(Et)VAVP DDAVP 1%PMC 4 ±n=6 DDAVP n=5 *: p<0.05, : p<0.01 Dunnett (c) V 2-18 d(c 2 ) 5 Tyr(Et)VAVP µg/kg 10 mg/kg V
26 (d) V 2 - ela camp Brattleboro V 2 - (5) (a) V 1a - V 1a - 21 V 2 - V 1a -Ki 76.3 nm V 1a nm 80 nmic ±0.35 µmadp4 µm 10 µm V 1a - (b) 23 1 mg/kg (c) in vitro 24,25 10 µm 70%IC 50 = 3.1 µm 56% 50%Ki 1.44 µm V 2 -Ki 9.42 nm
27 II M 1 M 2 M 3 A 1 A 2a A 2b α 1 α 2A α 2B α 2C β 1 β 2 β 3 AT 1 AT 2 0 B Type L Type D 1 D 2 -Long ET A ET B - GABA B Delta (δ) Kappa (κ) Mu (µ) K ATP 2 5T 1A 5T 2A 5T (IC 50 =3.1 µm) a VIP 0 (Ki=1.44 µm) b 10 µm 1 a 70% IC 50 1 b 4 Ki
28 (6) (a) V M1M V 2 - V 2 - ela 1,26,27,28 4,29,30 5 C3 C3 C3 Cl C3 C3 C C3 C3 C C3 C3 <M1> <M2> <M3> <M4> <M5> <M6> <M7> C3 C3 C3 C3 C3 C3 <M8> <M9> <M10> <M11> <M12> C3 C3 C3 <M13> <M14> <M15> <M16> V 2 - M1M5 V 2 - M1 M M3 M4 M5 M6 M7 V 2 - V 2 - M6 M7 M8M14 M15 V
29 V 2 - Ki, nm V 2 - (n) V 2 - (n) V 2 - (n) 9.42 ± ± ± M ± ± ± M ± ± ± M ± ± ± M ± ± ± M ± ± ± M6 I a 4 I a 5 I a 4 M7 I a 4 I a 4 I a 4 M ± ± ± 16 4 M9 I a 4 I a 5 I a 4 M10 I a 4 I b 4 I a 4 M11 I a 4 I b 4 I a 4 M12 I a 4 I b 4 I a 4 M13 I a 4 I b 4 I a 4 M ± ± ± M ± ± ± 45 4 M16 I a 3 I 50% a 10 µm b 1 µm ± V 2 - ela camp V 2-1,31 V 2 - camp [ 3 ]- 10 µm camp V V 2 - M8M14 M15 10 µm camp V
30 V 2 - ela camp V 2 -camp camp a camp b IC 50 (nm) (%) 230 ± 83 (4) 100 ± 5 (3) M1 31 ± 3 (4) 107± 13 (3) M2 110 ± 11 (4) 98 ± 6 (3) M3 346 ± 36 (4) 99 ± 5 (3) M4 626 ± 105 (4) 111 ± 9 (3) M5 549 ± 112 (4) 84 ± 5 (3) a 1 nm camp 50% b 10 µm camp % M6 M7 V 2 - ± (b) V 2 - SD ED 3 M2M5 V 2 -M1 V 2 -ED mg/kg 10 mg/kg M1 in vivo
31 SD 8 c 3 e 0.3, 1, 3 ED 3 a Ki b AUC (0-2h) t 1/2 d (mg/kg) (mg/kg) (nm) (µg h/ml) (h) M1 50% DMF f 0.3, 1, 3 M2 40% DMF f 3, 10, 30 M3 40% DMF f 3, 10, 30 M4 e 1, 3, 10 M5 50% DMF f 1, 3, ( ) 6.44 g ( ) ( ) ( ) 3.13 ( ) 2.99 ( ) (2-4h) (1-3h) (2-8h) (2-8h) (4-8h) (3-6h) a % b V 2 - c 10 mg/kg d e =10873 f g 3 ED 3 95% (c) V 2 -M1 M2 M3M4 M5 camp camp V 2 - (7) (a) V 2-5 R (+)- S (-)- V 2 - M1M4 M5 5 M2 M3 4 5 V 2 - V 2 - ela 1,26,33 4,29,30
32 5 V 2 - S (-)- R (+) M2M3 M5 V V 2 - Ki, nm V 2 - n V 2 - n V 2 - n 9.42 ± ± ± R(+)- 142 ± ± ± S(-) ± ± ± M ± ± ± R(+) ± ± ± S(-) ± ± ± M ± ± ± (4R,5S)-(+) ± ± ± (4S,5R)-(-) ± ± ± M ± ± ± (4S,5S)-(+) ± ± ± (4R,5R)-(-) ± ± ± 84 4 M ± ± ± R(+) ± ± ± S(-) ± ± ± M ± ± ± R(+)- 74.1± ± ± S(-) ± ± ± ± (b) SD 4 34 R (+)- S (-)- R (+)- S (-) ED mg/kg95% mg/kg95% (c) V 2 - S (-)- R (+)
33 in vivo
34 ICRWistar, Wistar/STartley, ew Zealand White M1M7 ICR M15 GLP (1) mg/kg p.o.300 mg/kg p.o mg/kg p.o. 6/ mg/kg p.o. 1/5 200 mg/kg p.o. 3/5 25 mg/kg p.o. 2/ mg/kg p.o. 4/ mg/kg p.o. GABA A GABA B mg/kg p.o mg/kg p.o mg/kg p.o mg/kg p.o mg/kg p.o. 100 mg/kg p.o mg/kg mg/kg p.o mg/kg C max µg/ml mg/kg p.o mg/kg i.v mg/kg i.v µm 10 µm 50 1 mg/kg i.v
35 10 mg/kg i.v. PQ ST T 10 mg/kg i.v.qrs QT 51 1 µm 30 µm 52 in vitro 200 mg/kg p.o µm 10 µm APA V max APD PQ QRS 300 mg/kg p.o mg/kg i.v mg/kg i.v mg/kg p.o. 30 mg/kg p.o. 100 mg/kg 1000 mg/kg 30 mg/kg mg/kg i.v. 58 (2) mg/kg i.v. 10 mg/kg i.v. M1 M mg/kg i.v M15 10 mg/kg i.v mg/kg i.v. M3 10 mg/kg i.v M4M7 M5 0.3 mg/kg i.v.m4 1 mg/kg i.v.m6 3 mg/kg i.v. M2M3 M7 10 mg/kg i.v.m5 0.3 mg/kg i.v. M4 1 mg/kg i.v.m1 3 mg/kg i.v. M3M6 M7 10 mg/kg i.v. M5 1 mg/kg i.v. M6 3 mg/kg i.v.10 mg/kg i.v.m7 10 mg/kg i.v.0.3 mg/kg i.v. M4 M5 1 mg/kg i.v. T 3 mg/kg i.v. ST QRS M5 3 mg/kg i.v. PR QT 10 mg/kg i.v. M3 T PR QT M7 ST T
36 (1) V 2 - V 2 - V 2 - V 2 -V 2 - camp camp camp V 2 - V 2 - V ,18 Brattleboro V 2 -camp ,83 (2) SIAD SIAD inappropriate V
37 DDAVP 1 ng/h SIAD 110 mg/kg 2 mg/kg 10 mg/kg 10 mg/kg CPM 7 4 CPM 84 SIAD 3 mg/kg 21 meq/l 10 mg/kg 30 meq/l 10 mg/kg meq/l 5 12 meq/l CPM SIAD (3) M1M5 V 2 - V 2 - V 2 -in vivo V 2 - AUC C max M1 M2 V 2 - M3M4 M5 AUC C max V
38 AUC C max M1 M2 M3 M1M2 M3 M14 V 2 - M1 M2 M1M4 M5 M1M2M4 M
39 V 2 - C max AUC 30mg a 10mg/kg 30mg/kg C max M M M M M M M M M M M M M M M M AUC M M M M M M M M M M M M M M M M V 2 - V 2 - Ki V 2 - Ki 1.00 AUC C max AUC C max 1.00 a 30mg *-003 # * V *: 新薬承認情報提供時に置き換えた
40 (4) V 2 - V 1a - V 2-1/8V 1a - Ki 1.44 µmic µm10 µm 56% V 2 - (5) 30 mg/kg p.o. 1 mg/kg i.v. 30 mg/kg 0.23 µg/ml 30 mg 10 C max 4 ng/ml 4 ng/ml129-* mg/kg p.o. 10 mg/kg i.v. M15 10 mg/kg i.v. 10 mg/kg i.v mg/kg p.o. 10 mg/kg i.v. 10 mg/kg i.v. (6) V 2 - SIAD *: 新薬承認情報提供時に置き換えた
41
42 PC-31260PC V , Binding study of PC-31260, its optical isomers, and its metabolites against [ 3 ]AVP binding to human vasopressin V 1a -receptors , Antagonistic action of PC-31260, its optical isomers, and its metabolites on cloned human vasopressin V 1b -receptors -in vitro binding study , PC-31260PC , Inhibitory effects of PC-31260, its optical isomers, and its metabolites on [ 3 ]AVP binding to canine vasopressin V 1a - and V 2 - receptors , Aquaretic effects of PC in comparison with furosemide, hydrochlorothiazide and spironolactone in rats , Aquaretic effects of PC in comparison with furosemide in conscious male beagle dogs , PC a , Aquaretic effects of PC by repeated oral dosing in rats , SIAD PC , Therapeutic effects of PC on hyponatremia in SIAD rats , Therapeutic effects of titration dosing of PC in SIAD rats , Laszlo FA, Csati S, Balaspiri L. Prevention of hyponatraemia and cerebral oedema by the vasopressin antagonist d/c 2 / 5 Tyr/Et/VAVP in rats treated with pitressin tannate. Acta Endocrinol 1984;106: Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988;34:
43 Brooks DP, Koster PF, Albrightson-Winslow CR, Stassen FL, uffman WF, Kinter LB. SK&F is a potent antidiuretic hormone antagonist in the rhesus monkey (Macaca mulatta). J Pharmacol Exp Ther 1988;245: Dubb J, Allison, Tatoian D, Blumberg A, Lee K, Stote R. SK&F is antidiuretic in man. Kidney Int 1987;31(abstract): Mah SC, ofbauer KG. Evaluation of the pharmacologic properties of a vasopressin antagonist in brattleboro rats. J Pharmacol Exp Ther 1988;245: Albrightson-Winslow CR, Caldwell, Brooks DP, uffman WF, Stassen FL, Kinter LB. Cyclooxygenase inhibition unmasks the full antidiuretic agonist activity of the vasopressin antagonist, SK&F , in dogsj Pharmacol Exp Ther 1989;249: Effects of PC-31260, DDAVP, and d(c 2 ) 5 Tyr(Et)VAVP on urine production in conscious brattleboro rats and sprague-dawley rats , PC , Lachant A, Smith MR, Xie ZJ, Romani WR. eterogeneity of the aggregation response of human platelets to arginine vasopressin. Am J ematol 1995;49: Effects of PC on the aggregation response of human platelets to AVP , PC , Effects of PC-129 against radioligand binding to various receptors and channels , Antagonistic action of PC-31260, its optical isomers, and its metabolites on cloned human oxytocin-receptors -in vitro binding study , Antagonistic action of presumed PC metabolites on cloned human vasopressin V 2 -receptors (o. 2) -in vitro binding study , Antagonistic action of PC metabolites on cloned human vasopressin V 2 -receptors (o. 4) -in vitro binding study , Antagonistic action of PC metabolites on cloned human vasopressin V 2 -receptors (o. 5) -in vitro binding study ,
44 Antagonistic action of identified and presumed PC s metabolites on rat vasopressin V 1a - and V 2 -receptors (o. 2) , Inhibitory effects of PC metabolites on [ 3 ]AVP binding to rat vasopressin V 1a - and V 2 -receptors (o. 3) , Efects of PC metabolites on camp production in human vasopressin V 2 -receptor-expressed ela cells , Aquaretic effects and serum concentrations of PC-31260, its optical isomers, and its metabolites after single intravenous administration in conscious rats , Antagonistic action of presumed PC metabolites on human vasopressin V 2 -receptors (o. 3) -in vitro binding study , Aquaretic effects of PC optical isomers,(r)-(+)-pc and (S)-(-)-PC-31260, in conscious male Sprague-Dawley rats , PC PC , PC PC , PC PC , PC fenbufen , PC , PC , PC , PC exobarbital , PC ,
45 PC writhing , PC PC , PC PC , PC PC , PC PC , PC PC , PC acetylcholinehistamine barium , PC PC , PC PC , PC PC , PC PC , PC PC , PC PC , PC , PC PC , PC PC , PC PC ,
46 PC PC , PC DM , PC DM , PC DM , PC SF , PC PC , PC PC , PC PC , PC DM-3111 strychnine , PC DM , PC DM-3105 strychnine , PC SF , PC DM , PC PC , PC PC ,
47 PC PC , PC DM , PC DM , PC DM , PC SF , Morel F. Sites of hormone action in the mammalian nephron. Am J Physiol 1981;240:F Chabardes D, Gagnan-Brunette M, Imbert-Teboul M, Gontcharevskaia, Montegut M, Clique A, et al. Adenylate cyclase responsiveness to hormones in various portions of the human nephron. J Clin Invest 1980;65: Ruggles BT, Maruyama, Werness JL, Gapstur SM, Bentley MD, Dousa TP. The vasopressin-sensitive adenylate cyclase in collecting tubules and in thick ascending limb of enle s loop of human and canine kidney. J Clin Endocrinol Metab 1985;60: Kleinschmidt-DeMasters BK, orenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981;211: Gross P, Reimann D, eidel J, Doke C, Prospert F, Decaux G, et al. The treatment of severe hyponatremia. Kidney Int 1998;53:S PC PC ,
48
49 JA V 2 - ela in vitro V 1a - ela in vitro V 1b - ela in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro camp V 2 - ela in vitro () CTD Vol
50 JA () camp V 2 - ela in vitro Brattleboro V () CTD Vol
51 JA CTD Vol. V 1a - in vitro () A 1 A 2a A 2b α 2A α 2B α 2C β 1 β 2 β 3 AT 1 AT 2 B 2 CGRP D 1 D 2 ET A ET B M 1 M 2 M 3 δµ in vitro T 1A 5T 2A 5T 3 VIP) L Ca K ATP a α 1 GABA B 2 1 κ ela in vitro
52 JA CTD Vol. V 2 - ela in vitro V 2 - ela in vitro V 2 - ela in vitro V 2 - ela in vitro V 1a - ela in vitro V 1b - ela in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro camp V 2 - ela in vitro camp V 2 - ela in vitro V 2 - ela in vitro
53 JA CTD Vol. V 2 - ela in vitro V 2 - ela in vitro V 2 - ela in vitro V 1a - ela in vitro V 1b - ela in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro V 2 - V 1a - in vitro
54 JA V 2 - V 1a - in vitro in vivo CTD Vol () ()
55 JA CTD Vol a writhing a GLP
56 JA CTD Vol. (3) in vitro in vitro a in vitro a a GLP
57 JA CTD Vol. (3) M a a a M a a a a GLP
58 JA CTD Vol. (3) M a a a M a a a M a a a a GLP
59 JA CTD Vol. (3) M a a a M a a a M a () a GLP
60 JA CTD Vol () () () () () writhing () () () ()
61 JA (mg/kg) V 2 -V 1a - in vitro V 1b - ela camp V 2 - V 1 a - V 2 - V 1 a - V 2 - ela in vitro in vitro V M V 1a M V 1b M V M V 1a M V M V 1a M in vitro M a b ± 9V 2 4V 1a V 1b [ 3 ]- V 2 - V 1a - V 1b - Ki V ± 0.85 nm Ki V 1a ± 22.7 nm [ 3 ]- V 2 - V 1a - Ki V ± 1.56 nm Ki V 1a -524 ± 119 nm [ 3 ]- V 2 - V 1a - Ki V ± 1.42 nm Ki V 1a -118 ± 11 nm 1 nm camp IC ± 83 nm
62 JA (mg/kg) 1, 3, 10, mg/kg 3100 mg/kg 3, 10, mg/kg 1, 3 mg/kg 3, 10, mg/kg a 28 3, mg/kg 3 mg/kg ()
63 JA (mg/kg) V 2 - camp V 2 - ela Brattleboro V 2-1, 3, , 4, 6, 8, a mg/kg 7 4 in vitro 10-6,10-5 M 3 camp V 2-30 Brattleboro V V () ()
64 JA (mg/kg) V 1a - in vitro M nm IC ± 0.35 µmadp V 1a () in vitro 10-5 M ela M in vitro a b ± M 1 10 µm 70%IC µmκ56% 10 µm 50% A 1 A 2a A 2b α 2A α 2B α 2C β 1 β 2 β 3 AT 1 AT 2 B 2 CGRP D 1 D 2 ET A ET B M 1 M 2 M 3 δµ 5T 1A 5T 2A 5T 3 VIP) L Ca K ATP α 1 GABA B [ 3 ]- Ki 1442 ± 447 nm
65 JA, #1 (mg/kg) V 2 -V 1a - V 1b - ela in vitro V M V 1a M V 1b M 3, 49 V 2 - V 1 a - V 2 - V 1 a - in vitro in vitro V M V 1a M V M V 1a M V 2 -V 1a - Ki M10.88 ± 0.11 nm2.04 ± 0.30 nm M21.88 ± 0.30 nm5.54 ± 1.15 nm M36.59 ± 0.50 nm8.45 ± 1.55 nm M422.5 ± 2.3 nm76.3 ± 14.2 nm M524.3 ± 3.0 nm89.4 ± 21.7 nm M6II M7II V 1b - 50% I10 µm 50% V 2 -V 1a - Ki M14.17 ± 1.01 nm41 ± 8.0 nm M262.1± 15.3 nm280 ± 55 nm M358.6 ± 12.3 nm649 ± 78 nm M417.8 ± 2.4 nm488 ± 108 nm M515.3 ± 4.4 nm506 ± 113 nm M6II M7II I1 µm 10 µm 50% V 2 -V 1a - Ki M13.97 ± 1.02 nm10.6 ± 2.2 nm M244.5± 11.9 nm64.7 ± 14.6 nm M396.7 ± 33.0 nm85.6 ± 13.2 nm M412.6 ± 3.5 nm154 ± 33 nm M519.6 ± 3.0 nm300 ± 28 nm M6II M7II I10 µm 50% a b ± #
66 JA V 2 - camp ela camp V 2 - ela, #1 (mg/kg) in vitro M 4 1 nm camp IC 50 M131 ± 3 nm M2110 ± 11 nm M3346 ± 36 nm M4626 ± 105 nm M5549 ± 112 nm M6 M7 in vitro 10-6,10-5 M 34 V 2 -M1, M2, M3, M4, M5, M8, M14, M15 camp M1M5 M6 M7 a b ± #
67 JA V 2 -V 1a - V 1b - ela in vitro, #1 (mg/kg) V M V 1a M V 1b M 45 V 2 -V 1a - Ki R(+)-142 ± 12 nm502 ± 100 nm) S(-)-3.52 ± 0.56 nm45.4 ± 11.6 nm M1 R(+)-1.45 ± 0.34 nm1.58 ± 0.46 nm S(-)-0.63 ± 0.07 nm2.04 ± 0.34 nm M2 (4R, 5S)-(+) ± 7.0 nm8.43 ± 1.55 nm (4S, 5R)-(-)-1.30 ± 0.17 nm3.67 ± 0.74 nm M3 (4S, 5S)-(+)-3.71 ± 0.13 nm6.19 ± 1.01 nm (4R, 5R)-(-)-33.7 ± 3.2 nm13.6 ± 1.7 nm M4 R(+)-19.2 ± 4.3 nm94.8 ± 31.8 nm S(-)-15.4 ± 3.7 nm80.9 ± 24.1 nm M5 R(+)-74.1 ± 9.9 nm282 ± 59 nm S(-)-13.9 ± 2.6 nm71.3 ± 22.4 nm V 1b - 50% a b ± #
68 JA V 2 - V 1 a - in vitro, #1 (mg/kg) V M V 1a M 45 V 2 -V 1a - Ki R(+)-74.3 ± 22.6 nm3890 ± 814 nm S(-)-3.24 ± 0.85 nm287 ± 54 nm M1 R(+)-8.87 ± 2.20 nm59 ± 15 nm S(-)-4.87 ± 1.62 nm41 ± 9 nm M2 (4R, 5S)-(+)-130 ± 9 nm295 ± 20 nm (4S, 5R)-(-)-4.37 ± 0.35 nm22 ± 2 nm M3 (4S, 5S)-(+)-53.1 ± 4.2 nm327 ± 5 nm (4R, 5R)-(-)-913 ± 90 nm1372 ± 34 nm M4 R(+)-11.5 ± 2.9 nm500 ± 88 nm S(-)-20.7 ± 2.2 nm315 ± 70 nm M5 R(+)-29.6 ± 4.2 nm1940 ± 340 nm S(-)-9.96 ± 2.54 nm313 ± 73 nm a b ± #
69 JA V 2 - V 1 a - in vitro, #1 (mg/kg) V M V 1a M 4 V 2 -V 1a - Ki R(+)-62.2 ± 16.7 nm333 ± 90 nm S(-)-3.06 ± 0.41 nm63.2 ± 4.6 nm M1 R(+)-10.0 ± 1.1 nm31.5 ± 7.0 nm S(-)-2.17 ± 0.45 nm17.1 ± 5.6 nm M2 (4R, 5S)-(+)-1234 ± 285 nm295 ± 39 nm (4S, 5R)-(-)-42.1 ± 16.9 nm50.7 ± 20.4 nm M3 (4S, 5S)-(+)-37.4 ± 3.1 nm65.6 ± 18.5 nm (4R, 5R)-(-)-668 ± 84 nm267 ± 108 nm M4 R-(+)-12.9 ± 1.9 nm248 ± 34 nm S-(-)-20.3 ± 3.1 nm79.7 ± 17.4 nm M5 R-(+)-41.2 ± 10.2 nm425 ± 70 nm S-(-)-9.10 ± 2.76 nm78.7 ± 23.7 nm 1, 3, 10 6 R (+)- S(-)- a b ± #
70
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72 JA / i ICR ii iii vi writhing ICR ICR ICR ICR ICR ZW a a (mg/kg) , GLP 300 mg/kg 300 mg/kg 100 mg/kg 300 mg/kg 10 mg/kg 30 mg/kg 30 mg/kg 100 mg/kg 100 mg/kg 300 mg/kg 300 mg/kg 100 mg/kg 300 mg/kg 100 mg/kg 300 mg/kg 100 mg/kg 300 mg/kg 100 mg/kg 30 mg/kg 100 mg/kg
73 JA / ICR ICR artley a (mg/kg) % 5 GLP GABA A 2 mg/kg i.p mg/kg p.o mg/kg t max 515 C max µg/ml 5 # artley in vitro , 15 # M M 10-5 M 5 a #1 # M 10-5 M
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75 JA / ICR Wistar/ST Wistar/ST Wistar Wistar ICR Wistar a a (mg/kg) GLP mg/kg 3 mg/kg mg/kg 3 mg/kg 3 mg/kg 10 mg/kg p 3 mg/kg 10 mg/kg p 3mg/kg 10 mg/kg 3000 mg/kg 10 mg/kg 30 mg/kg 100 mg/kg 100 mg/kg 10 mg/kg 30 mg/kg 30 mg/kg 3000 mg/kg
76 JA M1 M4 / ICR ICR ICR ICR a a (mg/kg) mg/kg 10 mg/kg 1 mg/kg 3 mg/kg GLP mg/kg 10 mg/kg 0.3 mg/kg 1 mg/kg 0.3 mg/kg 1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg ST QRS
77 JA / a (mg/kg) GLP M5 ICR ICR a mg/kg 10 mg/kg 0.3 mg/kg 0.3 mg/kg 0.3 mg/kg 1 mg/kg 0.3 mg/kg 1 mg/kg 3 mg/kg ST PR QRS QT
78 JA M3 / ICR ICR a a (mg/kg) GLP mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg PR QT
79 JA M2 M6 / ICR ICR ICR ICR a a (mg/kg) mg/kg 10 mg/kg 3 mg/kg 10 mg/kg GLP mg/kg 10 mg/kg 1 mg/kg 3 mg/kg 3 mg/kg 10 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg
80 JA M7 / ICR ICR M15 ICR a (mg/kg) ICR a GLP mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg 3 mg/kg 10 mg/kg ST T ()
81 JA / a (mg/kg) ICR writhing ICR ICR ICR ICR ICR ICR a # # GLP () () () () () () () () ()
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