PHARMACOLOGICAL PROFILE OF YMO87, A NOVEL NONPEPTIDE DUAL VASOPRESSINV-1A AND V-2 RECEPTOR ANTAGONIST, IN DOGS

The pharmacological profile of YM087 d][1]benzazepin-6-yl)carbonyl]-2- phenylbenzanilide monohydrochloride) was investigated in dogs. YM087 s howed high affinity for vasopressin V-1A and V-2 receptors in radiolig and receptor binding studies with dog platelets (V-1A) and kidney (V-2 ). Intravenously injected YM087 (3-100 mu g/kg) dose dependently inhib ited the presser response to exogenous vasopressin in anesthetized dog s. Intravenous (10-100 mu g/kg) and oral (30-300 mu g/kg) administrati on of YM087 dose dependently increased urine flow with little effect o n urinary sodium and potassium excretion in normally hydrated consciou s dogs. Concomitantly, the urine osmolality dropped below the plasma o smolality (300 mOsm/kg H2O). In contrast, intravenously injected furos emide (300 mu g/kg) increased urine flow with marked increases in urin ary sodium and potassium excretion, These results indicate that YM087 is the first orally effective dual vasopressin V-1A and V-2 receptor a ntagonist and that it will be a new tool in the investigation of the p hysiological and pathophysiological role of vasopressin in the cardiov ascular system and kidney. YM087 may be useful for the treatment of pa tients with congestive heart failure, renal diseases and water-retaini ng diseases.