Pharmacological characterization of RWJ-676070, a dual vasopressin V(1A)/V(2) receptor antagonist.
The dysregulation of arginine vasopressin (AVP) release and activation of vasopressin V(1A) and V(2) receptors may play a role in disease. The in vitro and in vivo pharmacology of RWJ-676070, a potent, balanced antagonist of both the V(1A) and V(2) receptors is described. RWJ-676070 binding and intracellular functional antagonist activity was characterized using cells expressing V(1A), V(1B) or V(2) receptors. Its inhibition of V(1A) receptor-mediated contraction of vascular rings and platelet aggregation was determined. V(2) receptor-medated aquaresis was determined in rats, dogs and monkeys. V(1A) receptor-mediated inhibitory activity was assessed in vivo in a vasopressin-induced hypertension model and in normotensive rats and in two hypertensive rat models. RWJ-676070 inhibited AVP binding to human V(1A) and V(2) receptors (Ki=1 and 14 nM, respectively). RWJ-676070 inhibited V(1A) receptor-induced intracellular calcium mobilization and V(2) receptor-induced cAMP accumulation with Ki values of 14 nM and 13 nM, respectively. The compound was slightly less potent against rat V(1A) receptors. RWJ-676070 inhibited V(1A) receptor-mediated vasoconstriction in rat and dog vascular rings and AVP-induced human platelet aggregation. Dose dependent aquaresis was demonstrated in rats, dogs and monkeys following oral administration. RWJ-676070 inhibited AVP-induced hypertension in rats but had no effect on arterial pressure in normotensive and spontaneously hypertensive rats but did decrease arterial pressure in Dahl, salt-sensitive hypertensive rats. RWJ-676070 is a new, potent antagonist of V(1A) and V(2) receptors that may be useful for treatment of diseases benefiting from balanced inhibition of both V(1A) and V(2) receptors.
Gunnet
Joseph W
JW
Johnson & Johnson Pharmaceutical Research & Development, Welsh and McKean Roads, Spring House, PA 19477-0776, USA.
Wines
Pamela
P
Xiang
Min
M
Rybczynski
Philip
P
Andrade-Gordon
Patricia
P
de Garavilla
Lawrence
L
Parry
Tom J
TJ
Cheung
Wai-Man
WM
Minor
Lisa
L
Demarest
Keith T
KT
Maryanoff
Bruce E
BE
Damiano
Bruce P
BP
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D013141:Spiro Compounds / Q000494:pharmacology*; D014661:Vasoconstriction; D014667:Vasopressins / Q000494:pharmacology
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; C526925:RWJ-676070; D013141:Spiro Compounds; D014667:Vasopressins