Behavioral effects of AR-R 15849, a highly selective CCK-A agonist.

The behavioral effects of AR-R 15849, a novel cholecystokinin agonist with high affinity and selectivity for the CCK-A receptor subtype, were examined. Initially, using an operant feeding paradigm to test for anorectic activity and specificity, acute administration of AR-R 15849 was found to alter the intake and pattern of feeding in a manner similar to prefeeding. Further, AR-R 15849 did not induce compensatory feeding as did CCK-8, and did not affect performance on running rates of responding, or motor activity on a running wheel, as did fenfluramine. In tests for subchronic anorectic activity, daily intraperitoneal injections of AR-R 15849 significantly reduced food intake in fasted rats over a 9-day test period with greater efficacy compared to its nonselective predecessor AR-R 14294 (formerly FPL 14294). The sustained decrease in food intake with AR-R 15849 treatment resulted in a significant reduction in body weight gain over 9 days. Finally, an experiment designed to determine the effect of caloric deprivation and subchronic drug exposure on the overall efficacy of AR-R 15849 indicated that pharmacological tolerance does not develop following subchronic treatment.

ARL 15849: a selective CCK-A agonist with anorectic activity in the rat and dog.

Cholecystokinin octapeptide (CCK-8) and the peptide analog ARL 14294, formerly FPL 14294, [Hpa(SO3H)-Met-Gly-Trp-Met-Asp-N(Me)Phe-NH2], have been reported to induce satiety by interaction with the CCK-A receptor subtype. ARL 15849 [Hpa(SO3H)-Nle-Gly-Trp-Nle-N(Me)-Asp-Phe-NH2] is an improved ARL 14294 analog with enhanced CCK-A receptor selectivity, greater stability, and a longer duration of action. The affinity of ARL 15849 for the CCK-A receptor (Ki = 0.034 nM) is 6,600 fold greater than for the CCK-B receptor (Ki = 224 nM), whereas CCK-8 and ARL 14294 are nonselective. Although comparable in potency to contract isolated gallbladder and induce pancreatic phosphatidylinositol hydrolysis, ARL 15849 is 3- and 100-fold more potent than ARL 14294 and CCK-8, respectively, to inhibit 3-h feeding in rats. The duration of feeding inhibition was significantly longer for ARL 15849 (>5 h), compared to equipotent doses of ARL 14294 (3 h), and CCK-8 (1 h). Intranasal administration of ARL 15849 inhibits feeding in beagle dogs with a greater separation between doses that induce emesis and those that inhibit feeding. Therefore, ARL 15849 is a potent, selective, intranasally active anorectic agent which may be useful in the treatment of eating disorders.

Neuroprotective actions of 2-amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) in animal models of hypoxia and global ischemia.

2-Amino-N-(1,2-diphenylethyl)-acetamide hydrochloride (FPL 13950) has been demonstrated to have good anticonvulsant efficacy and a relative lack of acute side effects in rodents. Similar in structure to remacemide hydrochloride, it was also shown to possess weak potency as an uncompetitive antagonist of N-methyl-D-aspartic acid (NMDA) receptors. In our study FPL 13950 was profiled preclinically as a potential neuroprotective agent with respect to lengthening the survival time of rodents exposed to hypoxia, as well as for ability to protect the vulnerable CA1 pyramidal neurons of the rat and dog from the consequences of global ischemia. Under conditions of hypoxia, pretreatment of rodents with FPL 13950 resulted in an extension in the time to loss of the righting reflex (rats) and mortality (rats and mice). This occurred whether the rats were maintained at ambient body temperature or made hyperthermic. When administered after 30 min of four-vessel occlusion global ischemia for periods of either 7 (b.i.d.) or 14 days (s.i.d.), FPL 13950 exhibited protection of the vulnerable CA1 hippocampal neurons in rat. In the 14-day treatment study the CA3 neurons were evaluated and FPL 13950 was found to prevent the lesser degree of ischemic-induced damage to this hippocampal region. In ischemic rats treated with FPL 13950 for 7 days, electrophysiological responses of CA1 neurons (orthodromic and antidromic population spikes, in vitro) were also preserved after FPL 13950 treatment. FPL 13950 was administered i.v. at 30 min after 8 min of clamping the ascending aorta in dogs, followed by a b.i.d./s.i.d. dosing regimen for 1 wk. Neuronal damage to CA1 was considerable in the saline-treated ischemic animals but significantly protected in dogs receiving FPL 13950. FPL 13950 continues to serve as a potential backup candidate for remacemide HCl which is currently in clinical trials for patients with stroke and epilepsy.

Anticonvulsant efficacy/safety properties of 2-amino-N-(1,2-diphenylethyl)acetamide hydrochloride.

2-Amino-N-(1,2-diphenylethyl)-acetamide-hydrochloride (FPL 13950) was profiled preclinically in rodents for efficacy against convulsions, as well as for acute safety/behavioral observations. FPL 13950 exhibited good oral efficacy and duration of action with respect to prevention of seizures elicited by maximal electroshock-shock in both rats and mice. Tolerance to protection against maximal electroshock and hexobarbital-induced sleep-time was not evident after subchronic drug administration. FPL 13950 also prevented convulsions/mortality in mice after i.v. dosing with N-methyl-D, L-aspartate, however, it was ineffective against other types of chemically induced convulsions, as well as bicorneal kindling. High oral doses produced neural impairment in both mice and rats and hyperactivity in rats. Sequential administration of yet higher doses elicited tonic/clonic convulsions culminating in death. During i.v. infusion of metrazol in mice, high i.p. doses of FPL 13950 shortened the latency to first twitch and clonus. No increase in the startle response or phencyclidine-like behavior was evident after oral dosing in rats.

Antianxiety properties of the angiotensin II antagonist, DUP 753, in the rat using the elevated plus-maze.

The angiotensin II receptor antagonist, DUP 753 (Losartan), was compared with diazepam for antianxiety properties in the rat using the elevated plus-maze. Oral diazepam (5 mg kg-1) resulted in a significantly greater number of entries of rats into the open arms of the maze, an increase in time spent in the open arms and a decreased time spent in the closed arms. Oral doses of DUP 753 likewise resulted in significantly greater numbers of entries into the open arms (active at 0.0001, 0.001, 0.01 and 0.1 mg kg-1), increased time spent on the open arms (active at 0.0001-0.01 mg kg-1) and a decreased time spent in the closed arms (active at 0.0001, 0.01 and 0.1 mg kg-1). Larger (1.0 mg kg-1) or smaller (0.00001 mg kg-1) doses of DUP 753 were not active.

Electrophysiologic effects of FPL 13210 on canine Purkinje fiber action potential duration and Vmax comparison to disopyramide.

The frequency-dependent effects of FPL 13210, a new disopyramide derivative, were examined in isolated canine cardiac Purkinje fibers paced at a frequency of 2 Hz and following abrupt changes in pacing cycle length. At 2 Hz, FPL 13210 depressed Vmax, while shortening action potential duration measured at 50% of repolarization (APD50) and not affecting duration measured at 90% of repolarization (APD90). These effects were concentration dependent over the range of 1-30 microM. The depression of Vmax produced by 5 microM FPL 13210 was not significantly different than that produced by 18 microM disopyramide while the preparations were paced constantly at 2 Hz. At these concentrations, recovery of Vmax was slowed by both FPL 13210 and disopyramide. The slow time constant estimated for this relation after exposure to FPL 13210 was approximately 6.5 times longer than that estimated following administration of disopyramide. In addition, APD90s evoked by early premature stimuli in the presence of 5 microM FPL 13210 were longer than those produced in the absence of drug when the diastolic intervals longer than 100 ms produced shorter APD90s after FPL 13210 administration. Therefore, when FPL 13210 is compared to disopyramide using concentrations selected to produce equivalent degrees of Vmax depression, FPL 13210 produced effects on APD90 that were opposite to those produced by disopyramide when the diastolic interval was longer than normal. These effects of FPL 13210 would suggest that this compound should be classified as a class Ic antiarrhythmic agent, unlike disopyramide, a class Ia antiarrhythmic agent.

Flavodilol: a new antihypertensive agent.

Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.