piperidines and pipamperone

Topics: Brain; Butyrophenones; Humans; Isoxazoles; Piperidines; Pyrimidinones; Randomized Controlled Trials as Topic; Receptors, Serotonin; Risperidone; Ritanserin; Schizophrenia; Schizophrenic Psychology; Serotonin Antagonists

To conduct a cost-efficient pilot study on the effect of low-dose pipamperone on the serotonin-2A receptor binding in a large animal model with conventional single-photon emission tomography modalities.. Three healthy drug-naive female Beagle dogs were scanned before and after administration of a single-dose pipamperone of 5 and 10 mg. Acquisition was performed under general anesthesia 90 min after injection of the specific radioligand 123I-5-I-R91150 with a triple head gamma-camera (Triad, Trionix). Binding index and receptor occupancy were calculated on the emission data after image fusion with the emission data from the individual 99mTc-ethyl cysteinate dimer perfusion scans to optimize frontal cortex delineation.. A dose-dependent reduction of the binding index was observed after single low-dose pipamperone, suggestive for competition of this cold compound with the radioligand for the 5-HT2A receptor. The calculated mean-binding serotonin-2A binding index in the frontal cortex was 1.47 before treatment and reduced to 1.28 after one dose of pipamperone 5 mg and to 1.08 after one dose of pipamperone 10 mg. The calculated occupancy was 40.4% after one dose of 5 mg pipamperone and 83% after one dose of 10 mg pipamperone.. This experiment supports the hypothesis that pipamperone, even in the low-dose range, significantly blocks serotonin-2A receptors. This study also demonstrates the value of the canine model to investigate the effects of drugs on neurotransmitter systems. Repeated nuclear imaging brain scanning experiments with different paradigms and medication doses are possible with conventional imaging equipment in a well-accepted laboratory species.

Topics: Animals; Antipsychotic Agents; Brain; Butyrophenones; Dogs; Female; Piperidines; Receptor, Serotonin, 5-HT2A; Tomography, Emission-Computed, Single-Photon

The 5-HT(2A) and 5-HT(2C) receptors belong to the same subtype of the G-protein coupled receptor family and have several agonist and antagonist ligands in common. To gain more insight into the differences in the regulation of the two receptors, we studied the effect of agonist and antagonist pre-treatment on radioligand receptor binding and 5-HT-induced inositol phosphate formation on rat 5-HT(2A) and rat 5-HT(2C) receptors stable expressed in NIH 3T3 cells. We compared short (15 min) and prolonged (48 h) pre-treatment of the cells with the natural agonist, 5-HT and with the antagonist pipamperone, which can be readily washed out. The rat 5-HT(2C) receptor showed an agonist-induced down-regulation (decrease in B(max) of labelled agonist and antagonist binding) and desensitisation (decrease in 5-HT-induced inositol phosphate formation and potency of 5-HT). Antagonist pre-treatment induced an increase in rat 5-HT(2C) receptor-mediated inositol phosphate formation as well as increased agonist and antagonist radioligand binding. These findings are consistent with the classical model of G-protein coupled receptor regulation. In contrast, the rat 5-HT(2A) receptor expressed in the same host cell behaved differently, unlike the classical model. Pre-treatment with 5-HT for 15 min and 48 h did not change receptor levels measured by radioligand binding, but the signal transduction response (inositol phosphate formation) was significantly reduced. Pre-treatment with the antagonist pipamperone for 15 min and 48 h caused an increase in antagonist radioligand binding but a reduction in agonist radioligand binding and a decrease in inositol phosphate formation and potency of 5-HT. Hence, the rat 5-HT(2A) receptor apparently undergoes agonist desensitisation without down-regulation of the total receptor number. Antagonist pre-treatment causes a paradoxical desensitisation, possibly by uncoupling of the receptor from G-proteins. The uncoupled receptor does not bind 5-HT in the nanomolar range but retains its antagonist binding properties. Paradoxical antagonist-induced desensitisation of rat 5-HT(2A) receptors has also been observed in vivo.

Topics: 3T3 Cells; Animals; Benzamides; Binding Sites; Binding, Competitive; Butyrophenones; Dose-Response Relationship, Drug; Ergolines; Gene Expression; Inositol Phosphates; Iodine Radioisotopes; Membranes; Mice; Piperidines; Radioligand Assay; Rats; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin; Serotonin Agents; Serotonin Antagonists; Time Factors; Tritium

In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak "dopamine" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Butyrophenones; Dogs; Dopamine D2 Receptor Antagonists; Haloperidol; Humans; In Vitro Techniques; Isoxazoles; Lysergic Acid Diethylamide; Motor Activity; Neostriatum; Oxygen Consumption; Piperidines; Rats; Risperidone; Schizophrenia; Serotonin Antagonists; Species Specificity; Tryptamines

The theory that activation of serotonin type 2 (5-HT2) receptors facilitates lordosis behavior in the female rat was tested. The 5-HT2 antagonists pizotefin, cyproheptadine, metitepine, and ketanserin were found to inhibit lordosis behavior in ovariectomized rats that had been primed with estradiol benzoate and progesterone. Pipamperone was ineffective. The 5-HT2 agonist quipazine was ineffective alone, but it reversed the inhibitory effects of pizotefin, cyproheptadine, and ketanserin. It did not reverse the effects of metitepine. The results support the theory of a facilitatory role for 5-HT2 receptors in lordosis behavior.

Topics: Analysis of Variance; Animals; Butyrophenones; Cyproheptadine; Estradiol; Female; Ketanserin; Methiothepin; Piperidines; Pizotyline; Posture; Progesterone; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Serotonin Antagonists; Sexual Behavior, Animal

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.

Topics: 5-Hydroxytryptophan; Animals; Brain Chemistry; Butyrophenones; Cinanserin; Ketanserin; Male; Myoclonus; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists

The potency for the inhibition of 5-hydroxytryptamine (5-HT)-induced human platelet aggregation by ketanserin, pipamperone, spiperone, cyproheptadine and BW 501 in vitro decreased as the reaction pH increased progressively from 7.4 to 8.6, the largest shift (X 1125) in IC50 value (pH 7.4: 4 X 10(-9) M; pH 8.6: 4.5 X 10(-6) M) being found for ketanserin. With such an alkaline pH-shift, the fraction of the ionized form of the drugs decreased, reduction of the inhibitory capacity and of the ionized fraction being strongly correlated. Ketanserin (40 mg orally, - 15 h) in human volunteers, completely inhibited the 5-HT-induced platelet aggregation measured ex vivo, when tested at a reaction pH of 7.4; without gassing with CO2 5% -O2 95%, the plasma pH became alkaline and the inhibitory potency of the drug was strongly reduced (-60%). This study demonstrates the importance of the reaction pH for the aggregation of human platelets induced by 5-HT and its inhibition by ketanserin.

Topics: Amidines; Blood Platelets; Butyrophenones; Cyproheptadine; Female; Humans; Hydrogen-Ion Concentration; Ketanserin; Kinetics; Male; Piperidines; Platelet Aggregation; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Spiperone

7-Azidoketanserin, a potent photoaffinity probe for serotonin-S2 receptors was shown to irreversibly photoinactivate histamine-H1 receptors as well. The photolabelling of H1-receptors could be prevented by several selective histamine-H1 antagonists. In guinea pig cerebellum, a brain area that is highly enriched in H1-receptors, photolabelling could be directed exclusively to these receptors by adding a high concentration of pipamperone, which selectively blocks serotonin-S2 receptors. In rat pre-frontal cortex, a region that is enriched in serotonin-S2 receptors, pyrilamine was used to block H1-receptors, thereby directing the photolabelling exclusively to S2-receptors.

Topics: Affinity Labels; Animals; Azides; Binding, Competitive; Butyrophenones; Cerebellum; Cerebral Cortex; Female; Guinea Pigs; Ketanserin; Photolysis; Piperidines; Pyrilamine; Rats; Rats, Inbred Strains; Receptors, Histamine; Receptors, Histamine H1; Receptors, Serotonin; Spiperone

Ligand binding studies have identified certain serotonin (5-HT) antagonists with selective affinity for 5-HT2 receptors and other serotonin antagonists with affinity for both 5-HT1 and 5-HT2 receptors. This study compared the actions of ketanserin and pipamperone, selective 5-HT2 receptor antagonists, with metergoline and methysergide, nonselective 5-HT antagonists, on two behavioral responses in rats that are produced by the activation of 5-HT receptors: 1) the head shake response and 2) the 5-HT syndrome. Both the selective and the nonselective 5-HT antagonists blocked the head shake response produced by 5-hydroxy-L-tryptophan. The order of relative potency was: metergoline greater than ketanserin greater than pipamperone greater than methysergide. All four antagonists also blocked the head shake response produced by the 5-HT agonist quipazine. In contrast, the symptoms of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine were blocked by pretreatment with the nonselective 5-HT receptor antagonists but not by the 5-HT2 receptor antagonists. The differential actions of 5-HT antagonists on these behavioral responses suggest that different 5-HT receptors are involved in the head shake response and the 5-HT syndrome. That the order of relative potency for these drugs to block the head shake response was the same as their reported affinity for the 5-HT2 receptor suggests that the 5-HT2 receptor is involved in the head shake response. In contrast, the ability of 5-HT antagonists with affinity for the 5-HT1 receptor to block the 5-HT syndrome and the inability of 5-HT2 receptor antagonists to block the syndrome suggests that this behavioral response probably involves the activation of 5-HT1 receptors.

Topics: Animals; Behavior, Animal; Butyrophenones; Ketanserin; Male; Metergoline; Methysergide; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Brain; Butyrophenones; Dogs; Isonipecotic Acids; Ketanserin; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Solubility; Species Specificity; Spiperone; Time Factors

Topics: Antipsychotic Agents; Butyrophenones; Chromatography, Gas; Humans; Isonipecotic Acids; Piperazines; Piperidines

Pimozide (0.04, 0.16, 0.63 and 2.50 mg/kg), haloperidol (0.01, 0.04, 0.16 and 0.63 mg/kg) and pipamperone (2.50, 10.0, 40.0 and 160 mg/kg) were given subcutaneously to rats, pressing a lever for brain-stimulation through electrodes implanted in the lateral hypothalamic region of the medial forebrain bundle. The lowest dose of each neuroleptic did not affect self-stimulation; the second dose inhibited the response rate by approximately 50%, whereas the two highest doses completely suppressed self-stimulation behaviour. The centrally acting anticholinergic dexetimide (0.63 mg/kg, s.c.) completly antagonized the pimozide-induced inhibition; the haloperidol-induced inhibition was also completely antagonized except at its highest doses, whereas the effects of the sedative neuroleptic pipamperone were not antagonized. These data are consistent with a presumed dopaminergic cholinergic striatal interaction and show brain self-stimulation to be an effective measure of neuroleptic-anticholinergic interaction.

Topics: Animals; Brain; Butyrophenones; Depression, Chemical; Dexetimide; Drug Interactions; Electric Stimulation; Haloperidol; Isonipecotic Acids; Male; Pimozide; Piperidines; Rats; Self Stimulation; Tranquilizing Agents