The pharmacological profile of
YM087 (4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin -6-yl) carbonyl]-2-phenylbenzanilide monohydrochloride) was investigated in dogs.
YM087 showed high affinity for
vasopressin V1A and
V2 receptors in radioligand receptor binding studies with dog platelets (V1A) and kidney (V2). Intravenously injected
YM087 (3-100 micrograms/kg) dose dependently inhibited the pressor response to exogenous
vasopressin in anesthetized dogs. Intravenous (10-100 micrograms/kg) and oral (30-300 micrograms/kg) administration of
YM087 dose dependently increased urine flow with little effect on urinary
sodium and
potassium excretion in normally hydrated conscious dogs. Concomitantly, the urine osmolality dropped below the plasma osmolality (300 mOsm/kg H2O). In contrast, intravenously injected
furosemide (300 micrograms/kg) increased urine flow with marked increases in urinary
sodium and
potassium excretion. These results indicate that
YM087 is the first orally effective dual
vasopressin V1A and
V2 receptor antagonist and that it will be a new tool in the investigation of the physiological and pathophysiological role of
vasopressin in the cardiovascular system and kidney.
YM087 may be useful for the treatment of patients with
congestive heart failure, renal diseases and water-retaining diseases.