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The antiemetic activity, gastric motor activity, and dopamine receptor effects of metoclopramide, dazopride, and sulpiride were assessed to establish if enhancement of gastric motility or antagonism of central dopamine receptors is the predominant action for drug-induced suppression of cisplatin-induced emesis. Emesis produced in dogs by cisplatin is antagonized by metoclopramide and dazopride. The antiemetic actions of metoclopramide and dazopride are associated with their ability to enhance gastric motor activity. Dazopride, unlike metoclopramide, has minimal dopamine receptor antagonist properties. Sulpiride is a potent dopamine receptor antagonist; however, it had no effect on the stomach and was ineffective in suppressing cisplatin-induced emesis.

A series of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents. Compounds were evaluated for calcium-channel-blocking activity by determining their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips. The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group. Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1. The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent. In most cases, substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency. The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine. Compounds were evaluated for antihypertensive activity in spontaneously hypertensive rats (SHR) at an oral dose of 30 mg/kg. Of the 55 compounds tested, only nine produced a statistically significant (p less than 0.05) reduction in blood pressure greater than 20%; all of these compounds had fluoro substituents in both rings of the diphenylmethyl group. One of the most active compounds in the SHR at 30 mg/kg was 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (63), which produced a 35% reduction in blood pressure and was similar in activity to nifedipine. At lower doses, however, 4-[bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11% at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.

An increase in blood glucose levels after the administration of chlorpromazine has been observed in several animal species including man (1-5). Other phenothiazines have been shown to exhibiit a hyperglycemic response when administered to rats (6). Neither a depression of the motor activity nor a reduced body temperature are decisive factors in the origin of the chlorpromazineinduced hyperglycemia ( 7 ) .Phenothliazine derivatives have been shown to release catecholamines from adrenal glands in vitro (8). The removal of the adrenal glands or the adrenal medulla from rats prevents the hyperglycemic action of chlorpromazine (6). These studies suggest that the primary mechanism of phenothiazineinduced hyperglycemia is through the release of epinephrine from the adrenal glands.Four phenothiazines, with varying CNS activity ( 9 ) ' were compared for their ability to induce hyperglycemia, to produce CNS depression and to release catecholamines from isolated adrenal glands. These stud' lies were done to test the hypothesis that catecholamine release is directly related to the hyperglycemia produced by various phenothiazine compounds. It was also of interest to determine whether the degree of CNS depression produced by these compounds was correlated with the degree of hyperglycemia associated with their use.Materials and Methods. Animals. Male albino mice, weighing 20-24 g (Laboratory Supply Co., Indianapolis), were used in the blood glucose and CNS depression 1This investigation was supported in part by an NIH Grant No. Pol-GM15005. 2 Recipient of Predoctoral Fellowship No. 1-FOl-GM 43, 285-01 from the National Institute of General Medical Sciences, NIH.studies. Prior to experimentation the mice were housed in groups of 20 with free access to food and water. In some experiments, bilateral adrenalectomy was performed 5 days prior to drug treatment and the animals were maintained on a regular diet with 0.9% sodium chloride in the drinking water.Determination of blood glucose. The animals were sacrificed by decapitation. Blood was collected in beakers wetted with oxalate, and then assayed for glucose by the glucose oxidase method?Evaluation of CNS depression. Depression of spontaneous motor activity was determined for groups of 5 mice using circular photocell activity cages (Woodward Research Corp., Herndon, Va.) .Perfusion of isolated adrenal glands. Isolated bovine adrenals were used to obtain a measure of the catecholamine releasing abilities of CPZ and its analogs, since it was not possible to use mouse adrenals for this purpose. Fresh bovine adrenal glands were obtained at a local abbatoir and placed on ice during transport. About 45-60 min postmortem and glands were cannulated through the adrenal vein and perfused in a retrograde manner with aerated Locke's solution (10) at 37". Flow rates were maintained at 5 ml/min using a multichannel metering pump (Harvard Apparatus Col.) . A perfusion period of 45 min was allowed to elapse prior to the addition of the drugs, dissolved in Locke's solution (10 ml). The number of ...