Effects of SL 65.0472, a novel 5-HT receptor antagonist, on 5-HT receptor mediated vascular contraction

5-hydroxytryptamine (5-HT) contracts vascular smooth muscle and pharmacological and molecular biological data suggest that these effects are mediated primarily by stimulation of 5-HT(1B) and 5-HT(2A) receptor subtypes. We have studied the properties of 7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-1-yl] ethyl]-1,2-dihydroquinoline-1-acetamide (SL 65.0472 ), a novel 5-HT receptor antagonist, in isolated vascular preparations contracted by 5-HT or sumatriptan. In canine isolated saphenous vein strips (putatively 5-HT(1B)-mediated contraction), SL 65.0472 antagonised sumatriptan-induced contractions in a competitive manner (pA(2) 8. 17+/-0.36). 5-HT contracts rabbit aorta by stimulation of 5-HT(2A) receptors. SL 65.0472 displaced the 5-HT concentration response curve in rabbit aorta rightwards with a significant reduction in maximum. The apparent pK(B) value was 8.58+/-0.18. 5-HT-induced contractions of human coronary arteries are mediated by a mixed population of 5-HT(1B) and 5-HT(2A) receptors. SL 65.0472 produced rightward parallel shifts of the 5-HT concentration response curves in all tissues studied (pA(2) 8.8+/-0.14, n=7). In conclusion, SL 65. 0472 is a potent antagonist of vascular smooth muscle contraction in vitro mediated by 5-HT receptor stimulation.     

M100907, a selective 5-HT(2A) receptor antagonist, attenuates phencyclidine-induced Fos expression in discrete regions of rat brain

5-HT and dopamine receptor antagonists have become widely used as atypical antipsychotics. Although 5-HT(2A) receptor antagonistic activity is thought to contribute to the atypical aspects of these agents, the precise mechanism remains unknown. M100907 (R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine -methanol), a selective 5-HT(2A) receptor antagonist, is reported to attenuate phencyclidine (PCP)-induced locomotion in rodents. For the purpose of identifying regions in which M100907 exerts its effect, we investigated the effects of M100907 on PCP-induced Fos expression in rat brain. PCP (5 mg/kg, subcutaneously, s.c.) induced Fos expression in the cingulate cortex area 3, the agranular insular cortex, the piriform cortex, the nucleus accumbens, the anterior paraventricular thalamic nucleus and the ventral lateral septal nucleus. Pretreatment with M100907 (0.5 mg/kg, s.c.) attenuated Fos expression induced by PCP in the nucleus accumbens core, the shell, the agranular insular cortex and the piriform cortex. M100907 did not induce Fos expression in any of the regions investigated including the dorsolateral caudate/putamen when given alone. These results indicate that 5-HT(2A) receptor antagonism attenuates Fos expression in a regionally specific manner in rat brain in the PCP model of psychosis.     

Pharmacological characterization of RP 62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist.

1. RP 62203 (2-[3-(4-(4-fluorophenyl)-piperazinyl)propyl]naphto[1,8- ca]isothiazole-1,1-dioxide) is a novel naphtosultam derivative which shows very high affinity for 5-HT2 receptors in the rat cerebral cortex (Ki = 50.0 pM). 2. RP 62203 is relatively selective for this sub-type of 5-hydroxytryptamine (5-HT) receptor, having lower affinity for the 5-HT1A receptor and very low affinity for the 5-HT, receptor. RP 62203 displayed low to moderate affinity for alpha 1-adrenoceptors, dopamine D2 receptors and histamine H1 receptors. 3. In vivo binding experiments demonstrated that oral administration of low doses of RP 62203 led to a long-lasting (greater than 6 h) occupation of cortical 5-HT2 receptors (ID50 = 0.39 mgkg-1). 4. In cortical slices from the neonatal rat, RP 62203 potently inhibited inositol phosphate formation evoked by 5-HT, with an IC50 of 7.76 nM. 5. The activity of neurones in the raphé and their responses to microiontophoretically applied 5-HT were studied with extracellular recording electrodes in the anaesthetized rat. RP 62203 potently and dose-dependently blocked excitations evoked by 5-HT when administered at doses of 0.5-4.0 mg kg-1, i.p. In contrast, neither 5-HT-evoked depressions nor glutamate-evoked excitations of raphé neuronal firing were blocked by RP 62203 at doses as high as 8.0 mg kg-1, i.p. 6. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) could be abolished by low doses of RP 62203 in mice (ED50 = 0.44 mg kg-1, p.o.) and in rats (ED50 = 1.54 p.o.). Similar results were obtained with mescaline and 5-hydroxytryptophan (5-HTP). 7. The potency of RP 62203 was compared with that of three other 5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ICI 170,809. In all models, RP 62203 showed similar activity to ritanserin, whilst either ICI 169,369 or ICI 170,809 was several fold less active. 8. It is concluded that RP 62203 is a potent and selective antagonist at 5-HT2 receptors in the rodent central nervous system.     

Effects of the 5-HT2 receptor antagonist, ritanserin, on biogenic amines in the rat nucleus accumbens.

The effects of acute ritanserin treatment on dopamine (DA) and serotonin (5-HT) release and metabolism were studied in tissue and microdialysis samples of the nucleus accumbens in rats. Administration of a moderate dose of ritanserin elicited decreases in DA and 5-HT in tissue with concomitant increases in extracellular fluid. These data show that selective 5-HT2 receptor antagonism modulates DA as well as 5-HT neurotransmission and adds support to the suggestion that 5-HT/DA interactions may be important in the treatment of psychoses.     

盐酸沙格雷酯对血管系统作用的研究进展

盐酸沙格雷酯(sarpogrelate hydrochloride,安步乐克)是新上市的5-HT 2 受体阻滞剂,其可能通过维持血管内皮细胞完整、防止血管平滑肌细胞增殖等对血管相关疾病具有重要作用.综述近几年来安步乐克对血管系统作用方面的研究,并讨论其作用特点及可能的作用机制.     

BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethylphenyl)piperazin1-yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT_1A (pK _i = 7.72) and 5-HT_2A (pK _i = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT_2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC₅₀ = 6.09) and in the hippocampus (pEC₅₀ = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK _i = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT_1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 {1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl)]piperazine, claimed to be 5-HT_1A receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex.On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the CAMP response in the cortex, while exerting concurrent agonism at 5-HT_1A receptors and antagonism at 5-HT_2A receptors. These characteristics might explain the peculiar behaviour of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons (see accompanying paper).     

Effects of 5-HT2 receptor antagonist on cycloheximide-induced amnesia in mice

A role played by serotonergic neuronal system in cycloheximide (CXM)-induced amnesia was studied in mice using a step-down passive avoidance task. CXM (30 mg/kg SC) given immediately after training caused impairment of memory. Nonselective serotonin (5-HT) antagonist methysergide and selective 5-HT2 antagonist ritanserin significantly attenuated impairment of memory caused by CXM. 5-HT1 antagonist (+/-)-pindolol had no effect on CXM-induced amnesia. The antiamnesic effect of ritanserin on CXM-induced amnesia was antagonized by 5-HT (ICV), but not by nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine and 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin at the dose level which did not cause the memory disruption. Scopolamine antagonized the antiamnesic effects of methysergide and ritanserin on CXM-induced amnesia. These results suggest that 5-HT2 receptors and cholinergic neuronal system may play an important role in memory formation.     

The novel 5-HT1A receptor antagonist, SDZ 216-525, decreases 5-HT release in rat hippocampus in vivo.

1. Recent evidence suggests that the novel compound SDZ 216-525 is a selective and possibly silent 5-HT1A receptor antagonist. Here we have examined the action of SDZ 216-525 on central 5-HT1A autoreceptor function. The experiments involved measurement of drug effects on extracellular 5-HT in the ventral hippocampus of the chloral hydrate anaesthetized rat by use of microdialysis. 2. Acute injection of SDZ 216-525 (0.1, 0.3, 1.0 and 3 mg kg-1, s.c.) caused a dose-related decrease in 5-HT output with an estimated ED50 of at least 0.3 mg kg-1. This ED50 value is 20-30 times greater than ED50 values previously obtained for 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and NAN-190. In comparison, SDZ 216-525 is reported to have slightly higher affinity for the 5-HT1A site than 8-OH-DPAT and NAN-190. 3. The inhibitory effect of SDZ 216-525 (1 mg kg-1, s.c.) on 5-HT was blocked by the 5-HT1/beta-adrenoceptor antagonist, (-)-pindolol (8 mg kg-1, s.c.) but not by a combination of the beta 1- and beta 2-selective adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg kg-1, each). 4. Although in several experimental models SDZ 216-525 has high affinity, selectivity and lacks intrinsic activity at the 5-HT1A receptor, our experiments show that the drug decreases extracellular 5-HT in ventral hippocampus of the chloral hydrate anaesthetized rat via a pindolol-sensitive mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist

We have evaluated the anti-platelet and vascular pharmacology of AR246686, a novel 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. AR246686 displayed high affinity binding to membranes of HEK cells stably expressing recombinant human and rat 5-HT2A receptors (Ki=0.2 nM and 0.4 nM, respectively). Functional antagonism (IC50=1.9 nM) with AR246686 was determined by inhibition of ligand-independent inositol phosphate accumulation in the 5-HT2A stable cell line. We observed 8.7-fold and 1360-fold higher affinity of AR246686 for the 5-HT2A receptor vs. 5-HT2C and 5-HT2B receptors, respectively. AR246686 inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC50=21 nM). Similar potency was observed for inhibition of 5-HT stimulated DNA synthesis in rat aortic smooth muscle cells (IC(50)=10 nM) and 5-HT-mediated contraction in rat aortic rings. Effects of AR246686 on arterial thrombosis and bleeding time were studied in a rat model of femoral artery occlusion. Oral dosing of AR246686 to rats resulted in prolongation of time to occlusion at 1 mg/kg, whereas increased bleeding time was observed at a dose of 20 mg/kg. In contrast, both bleeding time and time to occlusion were increased at the same dose (10 mg/kg) of clopidogrel. These results demonstrate that AR246686 is a high affinity 5-HT2A receptor antagonist with potent activity on platelets and vascular smooth muscle. Further, oral administration results in anti-thrombotic effects at doses that are free of significant effects on traumatic bleeding time.     

Pharmacological studies in vivo with ICI 169,369, a chemically novel 5-HT2/5-HT1C receptor antagonist

ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) has been tested in vivo for its potency and selectivity as an antagonist at 5-HT₂ and 5-HT_1C receptors. It caused a 50% inhibition of 5-HTP-induced head twitches in mice and fenfluramine-induced hyperthermia in the rat at approximately 1 mg/kg following parenteral administration. Results showed that ICI 169,369 had good oral bioavailability, since in the fenfluramine test the oral and s.c. ID₅₀ values were similar. ICI 169,369 was a selective antagonist of 5-HT-induced bronhoconstriction in the guinea-pig and 5-HT-induced pressor effects in the anaesthetised dog. In a series of other test in vivo the compound was shown to be devoid of significant activity at ₂- and ₂-adrenoceptors, dopamine (D₂), muscarinic (M₁) and histamine (H₁) receptors at 30–100 times its ID₅₀ values used in the 5-HT tests. Thus, ICI 169, 369 is a selective, orally active 5-HT₂/5-HT_1C antagonist that should prove useful in the analysis of the role of 5-HT in physiological and pathological states.     

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist,directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT_1A receptor agonist/5-HT_2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1–10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1–1000 g/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1–10 g/kg and 0.1–3 g/kg i.v. respectively, and reduced it at higher doses, 30–300 g/kg and 10–30 g/kg i.v., respectively.The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT_1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 g/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OHDPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.These findings suggest that BIMT 17 directly inhibits the electrical activity of medial prefronto-cortical neurons through its dual mode of receptor interaction.     

5-HT3 receptor antagonism by anpirtoline, a mixed 5-HT1 receptor agonist/5-HT3 receptor antagonist.

1. The aim of this study was to provide evidence that anpirtoline, which is an agonist at 5-HT1B and 5-HT1D receptors and also displays submicromolar affinity for 5-HT1A recognition sites, in addition, acts as an antagonist at 5-HT3 receptors. 2. In radioligand binding studies on rat brain cortical membranes, anpirtoline inhibited specific binding of [3H]-(S)-zacopride to 5-HT3 receptor recognition sites (pKi: 7.53). 3. In N1E-115 neuroblastoma cells in which [14C]-guanidinium was used as a tool to measure cation influx through the 5-HT3 receptor channel, the 5-HT-induced influx was concentration-dependently inhibited by anpirtoline. In this respect, anpirtoline mimicked other 5-HT3 receptor antagonists; the rank order of potency was ondansetron > anpirtoline > metoclopramide. 4. The concentration-response curve for 5-HT as a stimulator of [14C]-guanidinium influx was shifted to the right by anpirtoline (apparent pA2: 7.78). 5. In urethane-anaesthetized rats, anpirtoline inhibited (at lower potency than zacopride and tropisetron) the 5-HT- or phenylbiguanide-induced bradycardia (Bezold-Jarisch reflex), but did not induce this reflex by itself. 6. Intravenous infusion of cisplatin in the domestic pig caused a consistent emetic response which was antagonized by anpirtoline. 7. It is concluded that anpirtoline, which was previously characterized as a 5-HT1 receptor agonist also proved to be a 5-HT3 receptor antagonist in several experimental models and, hence, exhibits a unique pattern of properties at different 5-HT receptors.     

Effects of a 5-HT2A receptor antagonist, sarpogrelate on thermal or inflammatory pain

The effects of intrathecally and systemically administered 5-hydroxytriptamine (5-HT)(2A) receptor antagonist, sarpogrelate on acute thermal or formalin induced pain were examined. Male Sprague-Dawley rats with lumbar intrathecal catheters were tested with their tail withdrawal response to thermal stimulation (tail flick test) or their paw flinching and shaking response by subcutaneous formalin injection into the hind paw (formalin test) after intrathecal or intraperitoneal administration of sarpogrelate. 5-HT(2A) receptor agonist was used to antagonize the effects of sarpogrelate. In the tail flick test, only intraperitoneal administration induced analgesia. In the formalin test, both intrathecal and intraperitoneal administration were analgesic. The analgesic effects were inhibited by pretreatment with 5-HT(2A) receptor agonist. Motor disturbance and behavioral side effects were not observed. In conclusion, sarpogrelate might be analgesic on inflammatory induced acute and facilitated pain by intrathecal or systemic administration. However, only systemic administration could be effective on thermal induced acute pain.     

Effects of sarpogrelate,a novel 5-HT2 antagonist,on 5-HT-induced endothelium-dependent relaxations in porcine coronary artery

The aim of the present study was to examine the effects of sarpogrelate, a 5-HT2 antagonist, on 5-HT-induced endothelium-dependent relaxation in isolated porcine coronary artery preincubated with ketanserin (3 x 10(-6) M) and precontracted by U 46619 (5 x 10(-9) M) and compare its effects with other 5-HT2 antagonists such as ritanserin and cyproheptadine. The investigation showed that sarpogrelate (10(-7)-10(-5) M) had a weak antagonistic effect on 5-HT-induced relaxation and its effect was weaker than that of ritanserin (10(-9)-10(-7) M) and cyproheptadine (10(-8)-10(-6) M). The rank order of the antagonistic effects was: ritanserin > cyproheptadine > sarpogrelate. The study also showed that both sarpogrelate and ritanserin had no inhibitory effect on bradykinin-induced relaxation. In our previous study, we investigated the binding affinity of sarpogrelate, ritanserin and cyproheptadine to the 5-HT2A-receptor in rabbit cerebral cortex membranes and the pKi values found were 7.22, 8.98 and 7.54, respectively (M. Rashid et al., Jpn J Pharmacol 87, 189-194, 2001). Rank order of the calculated ratio of concentration of pA2 or pD'2 vs Ki was: sarpogrelate > ritanserin > cyproheptadine. Thus, these findings suggest that sarpogrelate has the lowest antagonistic effect on 5-HT-induced endothelium-dependent relaxation and the highest selectivity towards 5-HT2A receptor and might also be the safest drug with respect to its clinical implications in comparison with ritanserin and cyproheptadine.     

5-HT_(2B)受体阻断剂对心肌肥厚大鼠心肌5-HT含量及5-HT_(2B)受体表达的影响

目的观察5-HT2B受体阻断剂对去甲肾上腺素(norepinephrine,NE)诱导的心肌肥厚大鼠心肌中5-羟色胺(5-hydrotriptamine,5-HT)含量及5-HT2B受体表达的影响。方法雄性SD大鼠24只,随机分为3组,8只/组,分别为对照组、肥厚组、实验组。采用腹腔注射NE(1.5 mg/kg,2次/d,28 d)的方法建立心肌肥厚模型,自第15天起实验组腹腔注射SB204741(5-HT2B受体阻断剂;2 mg/kg,2次/d),连续注射14 d。对照组腹腔注射相同体积的生理盐水(2次/d,28 d)。检测各组左心室重量与体重之比(LVW/BW)、心肌组织中5-HT的含量及5-HT2B受体的表达情况。结果在NE诱导心肌肥厚过程中,应用SB204741干预可显著减轻心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。结论应用5-HT2B受体阻断剂可减轻NE诱导心肌肥厚的程度,降低心肌组织中5-HT的含量,并抑制5-HT2B受体表达的上调。     

Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.

Serotonin(6) (5-HT(6)) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, RO4368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, RO4368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.     

Effects of DAU 6215, a novel 5-hydroxytryptamine3 (5-HT3) antagonist on electrophysiological properties of the rat hippocampus.

1. The aim of the present study was to test the effects of DAU 6215 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]-octo-3-yl)-2,3-dihydro-2-ox o-1H- benzimidazole-1-carboxamide carboxamide hydrochloride), a newly synthesized, selective 5-hydroxytryptamine3 (5-HT3) antagonist, on the cell membrane properties and on characterized 5-HT-mediated responses of pyramidal neurones in the hippocampal CA1 region. 2. Administration of DAU 6215, even at concentrations several hundred fold its Ki, did not affect the cell membrane properties of pyramidal neurones, nor modify extracellularly recorded synaptic potentials, evoked by stimulating the Schaffer's collaterals. 3. Micromolar concentrations (15-30 microM) of 5-HT elicited several responses in pyramidal neurones that are mediated by distinct 5-HT receptor subtypes. DAU 6215 did not antagonize the 5-HT1A-induced membrane hyperpolarization and conductance increase, a response that was blocked by the selective 5-HT1A antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalamido)butyl- piperazine). Similarly, DAU 6215 did not affect the membrane depolarization and decrease in amplitude of the afterhyperpolarization, elicited by the activation of putative 5-HT4 receptors. 4. 5-HT increased the frequency of spontaneous postsynaptic potentials (s.p.s.ps) recorded in pyramidal neurones loaded with chloride. In agreement with previous observations, most of the s.p.s.ps were reversed GABAergic events, produced by the activation of 5-HT3 receptors on interneurones, because they persisted in the presence of the glutamate NMDA and non NMDA antagonists, D-aminophosphonovaleric acid (APV; 50 microM) and 6,7-dinitroquinoxaline-2,3-dione (DNQX; 25 microM), and were elicited by the selective 5-HT3 agonist, 2-methyl-5-HT (2-Me-5-HT, 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

The novel 5-HT2 receptor antagonist, RP 62203, selectively blocks serotoninergic but not dopaminergic-induced inhibition in the rat prefrontal cortex.

The influence of the novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, RP 62203, on serotoninergic neurotransmission was investigated using an in vivo electrophysiological technique. For this purpose, the ability of RP 62203 (1-3 mg/kg i.p.) to block the inhibitory responses of prefrontal cortical neurons induced by electrical stimulation of the median raphe nucleus was examined in anesthetized rats. In addition, the effects of RP 62203 on the dopaminergic inhibitory responses induced in the prefrontal cortex by stimulation of the ventral tegmental area and on the enhancement of these responses by lysergic acid diethylamide (LSD, a 5-HT2 receptor agonist, 30 or 60 micrograms/kg i.p.), were analyzed. RP 62203 blocked the inhibition induced by median raphe nucleus stimulation in a dose-dependent and reversible fashion. In contrast, RP 62203 failed to affect the inhibitory responses induced in prefrontal cortical cells by stimulation of the ventral tegmental area. However, the enhancement by LSD of the inhibition induced by stimulation of the ventral tegmental area in the prefrontal cortex was blocked by RP 62203. These results demonstrate that RP 62203 selectively blocks serotoninergic, but not dopaminergic, neurotransmission in the prefrontal cortex.     

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.     

Effects of the 5-HT2 receptor antagonist, ritanserin on hyperthermia and depletion of 5-HT in frontal cortex induced by a 5-HT releasing drug, p-chloroamphetamine (PCA) in mice

Effects of the 5-HT2 receptor antagonist, ritanserin on hyperthermia and depletion of 5-HT induced by the 5-HT-releasing drug, p-chloroamphetamine (PCA) were investigated. Ritanserin significantly suppressed PCA-induced hyperthermia in mice. PCA elicited decreases in 5-HT levels in the mouse frontal cortex. 5-HT reduction elicited by PCA was also attenuated by pretreatment with ritanserin. Since hyperthermia facilitates neurotoxicity induced by amphetamine analogue, ritanserin may inhibit PCA-induced 5-HT neurotoxicity by inhibiting hyperthermia.