bw-723c86 and 1-(3-chlorophenyl)piperazine

Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.

Topics: Animals; Blood Proteins; Brain; Cell Line; Guinea Pigs; Humans; Indoles; Male; Piperazines; Piperidines; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Substrate Specificity; Thiophenes; Thioxanthenes; Xanthenes

Chemotherapy with an anticancer agent generally causes gastrointestinal tract disorders such as vomiting and anorexia, but the mechanism remains unclear. Rikkunshito, a kampo preparation, is known to alleviate such adverse reactions. In this study, we attempted to clarify the mechanism.. We investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito and 5-HT antagonists. In addition, binding affinities of rikkunshito components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors.. Cisplatin, 5-HT, BW723C86 (5-HT2B-receptor agonist), and m-chlorophenylpiperazine HCl (5-HT2C agonist) markedly decreased plasma acylated-ghrelin levels, although 5-HT3 and 5-HT4 agonists had no effect. In contrast, 5-HT2B and 5-HT2C antagonists suppressed the cisplatin-induced decrease of plasma acylated-ghrelin level and food intake. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito was blocked by a ghrelin antagonist. Components of rikkunshito, 3,3',4',5,6,7,8-heptamethoxyflavone, hesperidin, and iso-liquiritigenin showed a 5-HT2B-antagonistic effect in vitro, and oral administration of rikkunshito suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level.. The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.

Topics: Acylation; Aminopyridines; Animals; Anorexia; Antineoplastic Agents; Body Weight; Chalcones; Cisplatin; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Eating; Flavones; Gastric Mucosa; Gastrointestinal Agents; Ghrelin; Hesperidin; Indoles; Male; Oligopeptides; Piperazines; Protein Binding; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Stomach; Thiophenes; Vagotomy

In this work we studied the responses and receptors involved in the effects of intra-arterial 5-hydroxytryptamine (5-HT) in the in situ autoperfused hindquarters of spontaneously hypertensive rats (SHR). Intra-arterial administration of the highest doses (50-1,000 ng/kg) produced a vasoconstrictor effect that was inhibited by ritanserin (a selective 5-HT2 receptor antagonist), SB 206553 (a selective 5-HT(2B/2C) receptor antagonist) and spiperone (a nonspecific 5-HT(1/2A) receptor antagonist), and was mimicked by alpha-methyl-5-HT (a selective 5-HT2 receptor agonist) and m-CPP (a selective 5-HT2C receptor agonist), but not by the intra-arterial administration of BW 723C86, a selective 5HT2B receptor agonist. SB 206553 and spiperone inhibited alpha-methyl-5HT-induced vasoconstriction in the hindquarters of SHR. Our data suggest that the vasoconstrictor response induced by 5-HT in the autoperfused hindquarters of SHR is mainly mediated by the activation of 5-HT2A and 5-HT2C receptors.

Topics: Animals; Dose-Response Relationship, Drug; Hindlimb; Indoles; Injections, Intra-Arterial; Injections, Intravenous; Male; Perfusion; Piperazines; Prazosin; Pyridines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin, 5-HT2; Regional Blood Flow; Ritanserin; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Receptor Agonists; Spiperone; Thiophenes; Vasoconstriction

Hypercortisolism and altered serotonergic function may account for the pathological symptoms seen in depression. This study examines the impact of 4 days continuous corticosterone treatment on 5-HT agonist-induced behaviour to delineate changes in 5-HT receptor function in the adult rat. The flat body posture, reciprocal forepaw treading, elevated corticosterone, hyperglycaemia, hypothermia and reduced hippocampal 5-HT induced by the 5-HT(1A) agonist 8-OHDPAT (0.3 mg/kg ip) were all significantly attenuated by the corticosterone implant. The elevation in plasma corticosterone and back muscle contractions evoked by the 5-HT(2A) agonist DOI (1 mg/kg ip) were attenuated, whilst wet-dog shakes were enhanced by corticosterone treatment. 5-HT(2B) agonist-induced behaviour and the hypolocomotion and hypophagia induced by the 5-HT(2C) agonist m-CPP (2.5 mg/kg ip) were unaltered but the mCPP-induced elevation in corticosterone was abolished by corticosterone treatment. Hypothalamic 5-HT receptors mediating corticosterone- and 5-HT(1A) receptors, whether on serotonergic nerve terminals or postsynaptic neurones, were downregulated by corticosterone treatment. In contrast, 5-HT(2A) receptors may be up- or downregulated dependent on whether they are on supraspinal or spinal neurones, respectively. A comparison of the brain region-dependent alteration in serotonergic function produced by hypercorticosterone in the rat with that seen in depression is discussed.

Topics: Amphetamines; Animals; Behavior, Animal; Blood Glucose; Body Temperature; Brain Chemistry; Corticosterone; Drug Implants; Eating; Indoles; Male; Motor Activity; Piperazines; Rats; Serotonin Receptor Agonists; Thiophenes

Clinical and preclinical studies suggest that 5-HT and nitric oxide (NO) mobilization within the trigeminovascular system is fundamental to the initiation of migraine attacks., e.g. m-chlorophenylpiperazine (m-CPP) and glyceryl trinitrate (GTN) induce headache in humans. 5-HT2B receptors are known to mediate NO-dependent vasorelaxation in peripheral blood vessels, raising the possibility that this receptor is implicated in the pathogenesis of the disease. Therefore, we measured the effects of 5-HT2B agonists (m-CPP or BW723C86) or GTN on trigeminal nerves by quantifying Fos expression in the rat TNC. m-CPP (0.1 mg/kg, i.v.) induced time-dependent elevations in Fos-LI in the rat TNC 2 h and 8 h after injection. In contrast, neither intravenous GTN (0.5 microg/kg per min, infused 20 min) nor BW723C86 (0.1 mg/kg, i.v.) increased Fos-LI at 2 h or 8 h after administration. These data are not consistent with the involvement of the 5-HT2B/2C receptors or NO in trigeminovascular activation, and by inference migraine, and suggest the contribution of some other unidentified pathway.

Topics: Animals; Genes, fos; Indoles; Migraine Disorders; Nitric Oxide; Nitroglycerin; Piperazines; Rats; Serotonin Receptor Agonists; Thiophenes; Time Factors; Trigeminal Caudal Nucleus; Vasodilator Agents

The effects of serotonin (5-hydroxytryptamine, 5-HT)(1/2) receptor agonists for 5-HT(1) and 5-HT(2) receptors on dark-phase ingestive behavior were evaluated in 12-h food-deprived, female Wistar rats. The amount of food and water consumed after 1, 2, 6 and 12 h was measured. The following agonists were tested: ipsapirone [preferred 5-HT receptor(s) and dose range in mg/kg, IP: 5-HT(1A) and 3-30, respectively], CP-94,253 (5-HT(1B); 0.3-3), TFMPP (5-HT(1B/2C); 0. 3-10), m-CPP (5-HT(2C/1B); 0.3-10), ORG 37684 (5-HT(2C); 0.3-10), BW 723C86 (5-HT(2B); 3-30) and DOI (5-HT(2A/2C); 0.3-3). Ipsapirone induced hyperphagia during the first hour of food access and hypophagia during the last interval. All other compounds induced dose- and time-dependent hypophagia. m-CPP and TFMPP induced the most marked reduction of food intake and were the only drugs inducing rebound hyperphagia. Except for m-CPP and TFMPP, effects on food intake could generally be dissociated from effects on water intake. The receptor profile of the compounds tested suggests that stimulation of 5-HT(1B), 5-HT(2C), 5-HT(2A) or 5-HT(2B) receptors results in hypophagia. As the less selective agonists were the more potent anorexics, it is suggested that simultaneous activation of these receptors results in synergistic effects on ingestive behavior. Additional antagonism studies are required to ascertain the proposed role of particular 5-HT receptor subtypes in the hypophagic effects of the tested compounds.

Topics: Amphetamines; Animals; Darkness; Dose-Response Relationship, Drug; Drinking; Drinking Behavior; Eating; Feeding Behavior; Female; Indoles; Piperazines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Thiophenes; Time Factors

Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Conditioning, Operant; Ethylamines; Fluorobenzenes; Indoles; Male; Mianserin; Piperazines; Piperidines; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Reinforcement, Psychology; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes

The mixed 5-HT2A/5-HT2B/5-HT2C receptor agonist, m-(chlorophenyl)piperazine (mCPP), elicited penile erections in rats, an action mimicked by the selective 5-HT2C receptor agonist, RO 60-0175 (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine), whereas the preferential 5-HT2B receptor agonist, BW 723C86 (1-[5-(thienylmethoxy)-1H-3-indoyl] propan-2-amine) was ineffective. The actions of mCPP and RO 60-0175 were dose-dependently abolished by the novel 5-HT2B/5-HT2C receptor antagonists, SB 200,646 (1-(1-methylindol-5-yl)-3-(3-pyridyl) urea) and SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3 -f]indole). In contrast, penile erections were not significantly affected by the selective 5-HT2B receptor antagonist, SB 204,741 (1-(1-methylindol-5-yl)-3-(3-methylisothiazol-5-yl)-urea) nor by the selective 5-HT2A receptor antagonist, MDL 100,907 ([R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-p iperidine-methanol]). These data provide rigorous pharmacological evidence that activation of 5-HT2C receptor elicits penile erections in the rat. This model should, thus, be of use for characterising novel ligands at this site.

Topics: Animals; Dose-Response Relationship, Drug; Ethylamines; Indoles; Male; Penile Erection; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes; Urea