SR 121463A, a potent and selective, orally active, nonpep-tide vasopressin V 2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V 2 receptors in rat, bovine and human kidney (0.6 K i [nM] 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (K i 0.26 0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [ 3 H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V 2 receptors. In comparison, the nonpeptide V 2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V 2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (K i in the 10 nanomolar range). Moreover , OPC-31260 exhibited a poor V 2 selectivity profile and can be considered as a V 2 /V 1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na and K excretions unlike that of known diuretic agents such as furosemide or hydrochloro-thiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattle-boro rats. Thus, SR 121463A is the most potent and selective , orally active V 2 antagonist yet described and could be a powerful tool for exploring V 2 receptors and the therapeutical usefulness of V 2 blocker aquaretic agents in water-retaining diseases. (J. Clin. Invest. 1996. 98:2729-2738.) Key words: SR 121463A • vasopressin • nonpeptide antagonist • V 2 receptor • aquaretic

The effect of a 21-day program of caloric restriction on cardiac reactivity and beta-adrenoceptor number was investigated in male Sprague-Dawley rats. Rats on the restricted diet (Restricted) exhibited significant decreases in body weight, epididymal fat pad, and retroperitoneal fat pad weight as well as the percent of body fat represented by these adipose tissue depots when compared with rats fed ad libitum (Fed). Fed rats exhibited significantly increased total heart weight and total heart protein, but the percent cardiac protein and ratio of heart weight to body weight were similar in Fed and Restricted rats. Isolated atria from Fed and Restricted rats developed similar chronotropic and inotropic responses over a range of isoproterenol concentrations. Although total beta-adrenoceptor number (fmol/heart) was greater in Fed rats, the concentration of beta-adrenoceptors (fmol/mg protein) was remarkably similar regardless of the dietary regimen. Therefore, despite significant decreases in body weight, body fat, and heart weight, the myocardium of Restricted rats maintained the capability of responding to isoproterenol as that of Fed rats, the mechanism of which is at least partially mediated through maintenance of beta-adrenoceptor concentration.

Ten derivatives of halo propanediol were tested orally for male antifertility effects in adult Sprague-Dawley rats. Six of these compounds were effective in inducing temporary sterility at a daily dose ranging from 2\m=.\5to 5 mg/rat. When administered over a minimum period of 7 days, these minimum effective doses did not interfere with the mating behaviour and spermatogenesis even during prolonged medication. However, at ten times the minimum effective dose, Compounds III (1-chloro-2,3-propanediol) and VII (1-chloro-2,3-bis[tetrahydropyran-2-yloxy]propane) caused severe testicular damage and irreversible sterility, while Compound X (4-[chloromethyl]-2-pentyl-1,3-dioxolane) did not. Our studies confirm that the presence of an \g=a\-chlorohydrin group is essential in halo propanediol derivatives for antifertility effects in male rats.

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