piperidines and seganserin

The acute administration of the neurosteroid precursor, progesterone (10 mg/kg, s.c.) produced significant hyperphagia in female mice as observed at 0.5-, 1-, 2- and 3-h time intervals. At this dose progesterone also produced significant increase in immobility period duration in Porsolt's forced swim test and nociceptive response in hot-plate and tail-flick tests. Treatment with direct (quipazine, 5 mg/kg, i.p.) and indirect (fluoxetine, 10 mg/kg, i.p.) acting serotonergic agents per se produced significant hypophagia, decrease in immobility period and induced analgesic effect in hot-plate and tail-flick test. Further, treatment with both fluoxetine (10 mg/kg, i.p.) and quipazine (5 mg/kg, i.p.) significantly reversed progesterone-induced hyperphagia, depression and algesia in the female mice. Pretreatment with seganserin, a 5-HT(2) receptor antagonist (2 mg/kg, i.p.) significantly reversed fluoxetine and quipazine-induced antidepressant and analgesic effects. Seganserin reversed quipazine-induced hypophagia but in a replicate study it failed to reverse fluoxetine-induced hypophagia. Further, seganserin, 2 mg/kg, i.p., significantly reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced hyperphagia, depression and algesia in hot-plate test. Seganserin also reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced algesia in hot-plate test. These data suggest that the modulation of progesterone-induced effects by these serotonergic agents possibly involve 5-HT(2) receptor mechanisms. Further, the study underscores the use of serotonergic agents for the treatment of eating and affective disorders caused by the regular changes or disturbances of ovarian steroid levels in females.

Topics: Analgesics; Animals; Antidepressive Agents, Second-Generation; Brain; Depression; Disease Models, Animal; Drug Interactions; Female; Fluoxetine; Hyperphagia; Menstrual Cycle; Mice; Mice, Inbred Strains; Motor Activity; Pain; Pain Measurement; Piperidines; Progesterone; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists

The present study was undertaken to examine the effect of 5-HT2A receptor antagonists on MK-801 (5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine)-induced stereotypy and hyperlocomotion. MK-801 (0.1, 0.25 and 0.5 mg/kg) dose-dependently increased stereotypy and locomotion in mice. The 5-HT2A receptor antagonists, ketanserin (2.5, 5 and 10 mg/kg) and ritanserin (0.5, 1 and 2 mg/kg), dose-dependently blocked MK-801 (0.5 mg/kg)-induced hyperlocomotion. Only the higher dose (2 mg/kg) of seganserin could block locomotor activity. Similarly, ketanserin (2.5, 5 and 10 mg/kg), ritanserin (1 and 2 mg/kg) and seganserin (0.5, 1 and 2 mg/kg) dose-dependently blocked MK-801 (0.5 mg/kg)-induced stereotypy. The results suggest the involvement of 5-HT2A receptors in MK-801-induced stereotypy and hyperlocomotion. The lack of effect on spontaneous locomotion further suggests that 5-HT2A receptor antagonists will be less prone to induce psychomotor side-effects.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Histamine H2 Antagonists; Ketanserin; Locomotion; Male; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Piperidines; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Stereotypic Movement Disorder

Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. Since neurochemical alterations may not have behavioural or electrophysiological consequences the contribution of the serotoninergic system to the pathogenesis of hepatic encephalopathy was explored.. The effects of drugs modulating serotoninergic neurotransmission, the nonselective serotonin receptor antagonist methysergide and the serotonin2 receptor antagonist seganserin were tested neuropharmacologically in thioacetamide-induced acute liver failure in rats.. Methysergide had no effect in control rats, but dose dependently increased motor activity in stage II-III hepatic encephalopathy by 232% (5 mg/kg methysergide), 531% (10 mg/kg) and 507% (20 mg/kg). In contrast, seganserin had no effect in encephalopathic rats.. It is suggested that the beneficial effects of methysergide are serotonin, receptor mediated. Overall the results suggest that serotoninergic mechanisms contribute to some of the behavioural manifestations of hepatic encephalopathy in this animal model.

Topics: Animals; Dose-Response Relationship, Drug; Hepatic Encephalopathy; Male; Methysergide; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thioacetamide

The effects of seganserin, a specific 5HT2 antagonist, on human sleep were assessed in two experiments and compared to the effects of temazepam and sleep deprivation. During daytime recovery sleep after sleep deprivation, seganserin did not significantly enhance visually scored slow wave sleep (SWS, stages 3 + 4) or the EEG power density in the delta frequencies. Under these conditions temazepam reduced the power density in the delta and theta frequencies. During nighttime sleep after a nap in the evening, seganserin caused an increase in SWS, a reduction in intermittent wakefulness, and an enhancement of the power density in the delta and theta frequencies during non-rapid eye movement (NREM) sleep. Temazepam induced a reduction in the power density in the delta and theta frequencies. It is concluded that the 5HT2 antagonist, seganserin, can induce SWS. However, since the spectral results showed that the changes in the sleep EEG were not identical to those induced by sleep deprivation it seems premature to conclude that 5HT2 receptors are primarily involved in NREM sleep regulation.

Topics: Adult; Anti-Anxiety Agents; Electroencephalography; Electromyography; Electrooculography; Humans; Male; Piperidines; Serotonin Antagonists; Sleep Deprivation; Sleep Stages; Sleep, REM; Temazepam

The experimental drugs butanserin (R 53393), ritanserin (R 55667), R 56413, flufylline (Sgd 195/78) and fluprofylline (Sgd 144/80) were evaluated with respect to their antagonism at postjunctional alpha 1- and alpha 2-adrenoceptors and 5-HT2-receptors in pithed rats. Moreover, affinity for [3H]mianserin, [3H]prazosin and [3H]yohimbine binding sites was assessed using rat brain preparations. In all experiments ketanserin was taken as a reference compound. It is concluded that of the compounds investigated butanserin is the most potent and selective alpha 1-adrenoceptor antagonist, whereas ritanserin was found to be a potent and selective 5-HT2-antagonist. Of the other compounds, fluprofylline was a very selective though not very potent alpha 1-adrenoceptor antagonist. The other compounds were less active and less selective in this respect.

Topics: Adrenergic alpha-Antagonists; Animals; Binding, Competitive; Blood Pressure; Brain; Decerebrate State; Histamine H2 Antagonists; Ketanserin; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Theophylline; Vasoconstriction

The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced head-twitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.

Topics: 5-Hydroxytryptophan; Animals; Anti-Anxiety Agents; Anxiety; Chlordiazepoxide; Diazepam; Disease Models, Animal; Histamine H2 Antagonists; Humans; Lysergic Acid Diethylamide; Male; Motor Activity; Piperidines; Pyrimidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists

Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced. It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Electric Stimulation; Hypertension; Ketanserin; Phenylephrine; Piperidines; Prazosin; Pyrimidines; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha; Ritanserin; Sympathetic Nervous System