Affinity For 5-HT2 Receptors Research Articles

High Affinity Binding of Azasetron Hydrochloride to 5-Hydroxytryptamine3 Receptors in the Small Intestine of Rats

The binding affinity of azasetron hydrochloride (azasetron) for the 5-hydroxytryptamine3(5-HT3) receptor in a tissue preparation of rat small intestine was investigated by using [3H]granisetron as a radioligand. Scatchard analysis of specific [3H]granisetron binding revealed a single population of saturable binding sites in the tissue preparation. At this site, azasetron was concentration-dependently competitive with [3H]granisetron, and it inhibited the specific [3H]granisetron binding with a Ki value of 0.33 nM. Azasetron has a high affinity for 5-HT3 receptor in the gastrointestinal organ, the very site of its antiemetic action against chemotherapy-induced emesis.

High affinity binding of azasetron hydrochloride to 5-hydroxytryptamine3 receptors in the small intestine of rats.

The binding affinity of azasetron hydrochloride (azasetron) for the 5-hydroxytryptamine3 (5-HT3) receptor in a tissue preparation of rat small intestine was investigated by using [3H]granisetron as a radioligand. Scatchard analysis of specific [3H]granisetron binding revealed a single population of saturable binding sites in the tissue preparation. At this site, azasetron was concentration-dependently competitive with [3H]granisetron, and it inhibited the specific [3H]granisetron binding with a Ki value of 0.33 nM. Azasetron has a high affinity for 5-HT3 receptor in the gastrointestinal organ, the very site of its antiemetic action against chemotherapy-induced emesis.

Radiosynthesis of a new radiobrominated ligand for 5HT2A receptors, a potential tracer for PET

4-Amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-2-methoxy-benzamide, a compound with high affinity for 5HT2-receptors, was radiobrominated in the 5-position of the methoxybenzamide group by electrophilic substitution. Hydrogen peroxide / acetic acid, peracetic acid and a mixture of both were tried as oxidants. Radiobromination with the hydrogen peroxide method gave a labelling yield of 80 % in the 5-position and 20 % in the 3-position without any side products. On the other hand the labelling methods based on the use of peracetic acid gave a more selective radiobromination in the 5-position, but with low yields and moreover generated radioactive and non-radioactive side products. N.C.A. radiobromide of high radio-chemical purity was obtained by an ion-exchange procedure on the target material solution coupled to a purification step using methanol. © 1997 John Wiley & Sons, Ltd.

The 5-HT3 receptor antagonist, RS-56812, enhances delayed matching performance in monkeys.

Substantial evidence indicates that serotonin receptors are involved in the regulation of acetylcholine release in CNS regions important to mnemonic processes, and may thus be exploited pharmacologically as targets for memory improvement. In the present study, the (R) and (S) isomers of a potent serotonin (5-HT3) receptor ligand, RS-56812 were evaluated for potential memory effects in five macaques trained to perform a delayed matching-to-sample (DMTS) task. While both isomers enhanced certain aspects of task performance, the (R) isomer produced more systematic improvements. This differential sensitivity to the isomers in regard to DMTS performance appears to parallel the higher 5-HT3 receptor affinity of the R enanantiomer. The results are consistent with a potential therapeutic role for RS-56812 in disorders involving cognitive decline.

Contrasting effects of SM-9018, a potential atypical antipsychotic, and haloperidol on c-fos mRNA expression in the rat striatum

SM-9018 (cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)hexahydro-1 H-isoindole-1,3(2 H)-dione HCl) is a potential atypical antipsychotic with high affinity for 5-HT2, dopamine D2 and 5-HT1A receptors. Northern blot analysis was performed to compare the effects of SM-9018 and of haloperidol on the striatal c-fos mRNA expression in rats. Haloperidol (0.3–30 mg/kg, p.o.) markedly increased the striatal c-fos mRNA levels (about eight-fold at 30 mg/kg), the increase being abolished by lesioning of dopamine neurons with 6-hydroxydopamine. In contrast, SM-9018 produced only a slight increase (about two-fold) in c-fos mRNA expression at doses up to 30 mg/kg (p.o.). The 5-HT2 receptor antagonist, ritanserin (0.1–3 mg/kg, i.p.), dose-dependently attenuated the haloperidol-induced c-fos expression, but the putative 5-HT1A receptor antagonist, NAN-190 (1-(2-methoxyphenyl)-4-(4-(2-phethalimmido)butyl)piperazine HBr; 1–10 mg/kg, i.p.), did not. These findings suggest that SM-9018 is weaker than haloperidol for induction of striatal c-fos mRNA expression, to which the 5-HT2 receptor blocking activity of SM-9018 seems to contribute.

Mirtazapine : A Review of its Pharmacology and Therapeutic Potential in the Management of Major Depression.

Mirtazapine : A Review of its Pharmacology and Therapeutic Potential in the Management of Major Depression.

D1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area

Repeated intermittent exposure to amphetamine produces long-term enhancements in the ability of this drug to produce locomotion and increase extracellular dopamine (DA) in the nucleus accumbens (NAcc). Three experiments were conducted to evaluate the role played by D1 DA receptors in the production of these changes in response to amphetamine. Rats were preexposed to amphetamine, alone or with a DA receptor antagonist, and tested for sensitization 1-3 weeks after the last drug injection. On the test for sensitization, locomotor (experiments 1 and 2) and NAcc DA (experiment 3) responses of the animals to a systemic amphetamine injection were assessed. In the first experiment, systemic injections of the D1 DA receptor antagonist SCH23390, but not other DA receptor antagonists with greater affinity for D2 DA and 5-HT2 receptors, blocked the development of locomotor sensitization produced by systemic injections of amphetamine. In the second experiment, locomotor sensitization induced by infusion of amphetamine into the ventral tegmental area (VTA) was blocked when these injections were preceded by systemic injections of SCH23390. Finally, in experiment three, co-injecting SCH23390, but not its inactive enantiomer, with amphetamine into the VTA during preexposure prevented sensitization of the NAcc DA response to this drug. These results indicate that while D2 DA receptor activation is not necessary for the induction of locomotor sensitization to amphetamine, D1 DA receptors located in the VTA play a critical role in the development of sensitized locomotor and NAcc DA response to this drug.

Benzoxazines. II. Synthesis, conformational analysis, and structure--activity relationships of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives as potent and long-acting serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1,4-benzoxazine ring with a 1,4-benzthiepine ring or seven-membered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1,4-benzoxazine ring increased the antagonistic activities (dimethyl > methyl > dihydro > phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3,4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2,2, 4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki = 0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold--Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.

A neurochemical basis for the antipsychotic activity of loxapine: Interactions with dopamine D1, D2, D4, and serotonin 5-HT2 receptor subtypes

Loxapine is a typical neuroleptic that shows great structural and functional homology to the atypical antipsychotic clozapine. Chronic loxapine treatment is usually associated with extrapyramidal symptoms (EPS), whereas clozapine treatment is not. Conversely, loxapine does not produce the agranulocytosis that often results from protracted clozapine treatment. Earlier studies of loxapine have usually implicated D2 receptor blockade as the cause of the tardive dyskinesia that occurs with chronic treatment. More recently, loxapine's ability to potentiate serotonergic neurotransmission has also been implicated. In this study, the pharmacological affinities of loxapine for the dopamine D1, D2, D4, as well as serotonin-2 (5-HT2) and NMDA receptor subtypes, were investigated through direct radioreceptor assays. The findings indicate that loxapine displays an extremely strong binding affinity for dopamine D4 and serotonin 5-HT2 receptors, which suggests that both serotonergic and dopaminergic mechanisms contribute to the antipsychotic drug action and EPS associated with loxapine in the treatment of schizophrenia.

Movement disorders in schizophrenia and implications for the use of newer antipsychotics

Olanzapine is a new antipsychotic drug with affinity for 5-HT2, D2, D1, and muscarinic receptors. Positron emission tomography and the radioligands [11C]raclopride and [11C]NMSP were used to measure D2 and 5-HT2 receptor occupancy in three healthy subjects after 10 mg olanzapine orally. After seven hours D2 receptor occupancy was 63%, 62% and 59%, respectively. After 9.5 hours 5-HT2 receptor occupancy was 74%, 86% and 92%. D2 and 5-HT2 receptor occupancy was comparable to that found in patients continuously treated with clozapine. Clinical efficacy has been demonstrated for olanzapine in the dose range 5 to 15 mg per day. Extrapolation from our present observations after a 10 mg single-dose suggest, that at the lower end of the clinically examined dose range the D2 and 5-HT2 receptor occupancy should be similar to that induced by standard doses of clozapine. Detailed evaluation of the doseresponse characteristics of olanzapine and direct clinical comparison to clozapine will thus provide valuable leads to the clarification of atypical antipsychotic action.

Structure-activity relationships of a series of novel (piperazinylbutyl)thiazolidinone antipsychotic agents related to 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate.

HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.

Design and synthesis of 6-chloro-3,4-dihydro-4-methyl-2H-1,4-benzoxazine-8-carboxamide derivatives as potent serotonin-3 (5-HT3) receptor antagonists.

Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT3) receptor binding affinity. The 5-HT3 receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromatic moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist. Consequently, a new series of 3,4-dihydro-2H-1,4-benzoxazine-8-carboxamides was obtained and these compounds were found to be more potent than 3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxamides. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3,4-dihydro-4-methyl-2H-1,4 -benzoxazine-8-carboxamide showed a high affinity for 5-HT3 receptors K(i) = 0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED50 = 0.089 micrograms/kg i.v.) in rats.

Evaluation of the receptor selectivity of the H3 receptor antagonists, iodophenpropit and thioperamide: an interaction with the 5‐HT3 receptor revealed

1. In the present study we evaluated the receptor selectivity of the potent histamine H3 receptor antagonist, iodophenpropit (IPP) in comparison with the prototype antagonist, thioperamide. 2. IPP proved to be a potent competitive H3 receptor antagonist as measured against (R)-alpha-methylhistamine-induced inhibition of electrically-evoked contractions of the guinea-pig jejunum (pA2 = 9.12 +/- 0.06, Schild slope: 1.0 +/- 0.1, n = 8). In the same assay, thioperamide was slightly less potent (pA2 = 8.9 +/- 0.2). 3. In radioligand binding studies, IPP showed a high affinity for the H3 receptor. Displacement of [125I]-IPP binding to rat cortex membranes by unlabelled IPP resulted in a Ki value of 0.97 +/- 0.06 nM (n = 3). In contrast, IPP showed only a weak affinity for the histamine H1- and H2 receptor. Displacement of [3H]-mepyramine and [125I]-iodoaminopotentidine binding to respectively guinea-pig H1- and human H2 receptors by IPP resulted in Ki values of 1.71 +/- 0.32 microM (n = 3) and 2.28 +/- 0.81 microM (n = 3). For thioperamide the affinities for the H1-, H2- and H3 receptor were respectively > 10 microM, > 10 microM and 4.3 +/- 1.6 nM (n = 7). 4. Testing IPP and thioperamide in 39 different receptor binding assays revealed that IPP showed relatively high affinity for the 5-hydroxytryptamine 5-HT3 receptor (Ki = 11 +/- 1 nM, n = 3), the alpha 2-adrenoceptor (Ki = 120 +/- 5 nM, n = 3) and the sigma receptor (Ki = 170 +/- 70 nM, n = 3). Thioperamide showed relatively high affinity for the 5-HT3 receptor (Ki = 120 +/- 30 nM, n = 3) and the sigma receptor (Ki = 180 +/- 90 nM, n = 3). 5. Due to the low density of histamine H3 receptors in the brain, the interaction of IPP with the 5-HT3-, the alpha 2- and the sigma receptor might interfere with [125I]-IPP binding to rat cortex membranes. Yet, in this preparation [125I]-IPP binding was not influenced by ondansetron, yohimbine or haloperidol. The interaction with the 5-HT3 receptor was not restricted to IPP or thioperamide, but was alsofound with other H3 receptor antagonists. The potent H3 receptor agonist imetit, a compound belongingto the same chemical class of IPP, also interacted with the 5-HT3 receptor (Ki = 240 +/- 40 nM). In contrast,histamine or the H3 receptor agonist, (R)-a-methylhistamine showed no affinity for the 5-HT3 receptor.7 In the guinea-pig isolated ileum, imetit evoked concentration-dependent contractions, resulting in apD2 value of 4.72 +/- 0.03 (n = 9). The contractions were antagonized by ondansetron, yielding a pA2 valueof 7.1 +/- 0.1 (n = 9). Similarly ondansetron antagonized the contractions evoked by the 5-HT3 receptoragonist, 2-methyl-5-HT with a pA2 value of 7.3 +/- 0.1 (n = 4). IPP and thioperamide did not mimic 2-methyl-5-HT but non-competitively inhibited the 2-methyl-5-HT-induced contractions of thispreparation.8 In an in vivo model for 5-HT3 activity, the Von Bezold Jarisch reflex, thioperamide showedantagonism in low dosages, which correlated well with the affinity for the 5-HT3 receptor site. Yet, athigher dosages no further 5-HT3 receptor antagonism was observed. For IPP no 5-HT3 receptor activitycould be observed in vivo.9 In the present study we showed that many H3 receptor compounds, that are regarded as highlyselective (including the prototype drug, thioperamide), also interact with the 5-HT3 receptor, albeit athigher drug concentrations.Keywords.: Histamine H3-receptor; iodophenpropit; thioperamide; receptor selectivity; 5-hydroxytryptamine 5-HT3 receptor;guinea-pig intestine; rat brain; Von Bezold Jarisch reflex

Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.

A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.

5‐HT2 receptor‐controlled modulation of medullary respiratory neurones in the cat.

1. The effects of the 5-HT2 receptor agonist alpha-methyl-5-HT were studied on the membrane of expiratory (E2) and post-inspiratory (PI) neurones, by intracellular recordings in the caudal medulla of anaesthetized cats. 2. Ionophoresis of alpha-Me-5-HT depolarized membrane potential and increased action potential frequency in a majority of neurones tested. Depolarization of neurones by alpha-Me-5-HT was accompanied by increased input resistance throughout all phases of the respiratory cycle. These effects were antagonized by ionophoresis of cinanserin, a receptor-blocking agent with high affinity for 5-HT2 receptors. 3. E2 neurones were voltage clamped to measure membrane current changes induced by alpha-Me-5-HT ionophoresis. alpha-Me-5-HT induced a net inward current by reducing inspiratory-phase outward currents and increasing expiratory-phase inward currents. These changes were equivalent with steady membrane depolarization, decreased inspiratory phase membrane hyperpolarization and increased expiratory drive potential recorded from the same neurones in current clamp. 4. The effects of alpha-Me-5-HT are consistent with activation of 5-HT2 receptors on E2 and PI neurones leading to blockade of synaptically activated and persistent conductances to potassium ions.

Platelet Binding Characteristics Distinguish Placebo Responders from Nonresponders in Depression

To determine whether there are characteristics distinguishing placebo responders from nonresponders, we studied 37 outpatients meeting DSM-III-R criteria for depression who were enrolled in controlled drug trials and 14 control subjects. Clinical data and blood samples were collected on admission and after a 7- to 10-day placebo washout. All patients experiencing a 40% drop in the Hamilton Rating Scale for Depression (HRSD) at the time of the second evaluation were considered placebo responders. There were no statistically significant differences between the two groups in clinical variables. Platelet markers distinguished the groups: Most notably, placebo nonresponders had the lowest 5-HT uptake site density values, placebo responders had intermediate values, and normal controls had the highest values. Placebo responders and placebo nonresponders had higher 5-HT uptake affinity values. No significant differences were observed among the groups in platelet 5-HT2 receptor site density or affinity values. These results suggest that platelet serotonin characteristics, but not common clinical characteristics, may distinguish depressed patients who do and do not respond to placebo.

Neuroimaging correlates of genetic marker for schizophrenia

hagen), and is being developed as an antipsychotic in the United States by the Psychopharmacology Venture of Ablxnt Laboratories. Sertindole is a potent antagonist with nanomolar affinities for dopamine D2, serotonin 5-HT2, and norepinephrine alpha-1 receptors. In vivo electrophysiological animal studies of sertindole have shown a 100-fold greater selectivity for ventral tegrnental area dopaminergic neurons over substantia nigra pars compacta neurons; thus, it is hypothesized that sertindole will be an effective antipsychotic agent with minimal neurological side effects. Sertindole study M93-098 is a phase 111, double-blind, placebo-controlled, fixed-dose, Haldol© (halopoeridol)-referenced (16 mg daily), randomized, 8-week trial of two doses of sertindole (20 and 24 mg daily) in schizophrenic patients. Twenty-nine centers in the United States will enroll approximately 400 patients. Efficacy will be assessed primarily by the PANSS total score. Effects on motor function will be assessed, as compared to Haldol, by the appearance of motor system adverse effects, the use of benztropine mesylate and several specific rating scales (SAS, BAS, and ALMS). Safety will be assessed by adverse event monitoring, clinical laboratory analysis, and electrocardiograms. The results of this study will be presented.

Altered cyclic amp response to forskolin and cholera toxin after protein kinas C activation in EBV-transformed B-lymphocytes from schizophrenics

Amperozide (FG 5606, N-ethyl-4-[4′,4′-bis(p-fluorophenyl)butyl]-1-piperazine-carboxamide) is an atypical antipsychotic drug which has relatively weak in vitro affinity for striatal dopamine2 (D2) receptors and strong affinity for cortical 5-HT2 receptors. The in vivo affinity for 5-HT2 binding sites in rat cortex was 1.1 mg/kg. In striatum or olfactory tubercle, doses of amperozide up to 40 mg/kg did not displace radioligand binding to D2 receptors. Amperozide, haloperidol and ritanserin had similar in vivo potency in blocking the 5-HT2 binding site, but only haloperidol displaced D2 receptor binding. Based on the clinically effective dose of amperozide (0.14–0.28 mg/kg per day), it is suggested that the antipsychotic effect of amperozide is related, in part, to its in vivo interaction with the 5-HT2 receptor and that amperozide cannot be expected to exert its antipsychotic action by blockade of D2 receptors in the striatum or limbic regions.

A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 receptors.

Risperidone is a benzisoxazole derivative with antipsychotic activity that is chemically unrelated to other currently available antipsychotic agents. Its neuropharmacological properties, characterized by potent central antagonism of both serotonin 5-HT2 and dopamine D2 receptors, also differ from those of most other antipsychotic drugs. The pharmacokinetics of risperidone are well understood, having been studied in healthy subjects as well as in psychotic patients. The absolute oral bioavailability of risperidone is nearly 70%, and after oral administration, it is rapidly absorbed with the plasma level reaching a peak at about 1 h. 9-Hydroxyrisperidone, one of the metabolites of risperidone, is equally active with the parent compound and so the clinical activity of a dose of risperidone is due to the combined actions of both moieties. The plasma concentrations of risperidone and its active metabolite remain dose proportional even at doses exceeding the therapeutic range. In clinical trials with chronic schizophrenia patients, risperidone has an overall therapeutic activity comparable with that of haloperidol, but at doses that produce similar improvements in the positive symptoms of schizophrenia, risperidone has a greater effect on the negative symptoms and produces less extrapyramidal side effects than does haloperidol. However, additional controlled clinical studies are needed before the claims that risperidone is therapeutically superior to haloperidol can be considered to be established firmly. Although risperidone is effective in acute schizophrenia and in non-treatment-resistant schizophrenics, studies adequately comparing risperidone with clozapine in treatment-resistant schizophrenic patients remain to be published. In addition, risperidone has been reported to be of value in patients with schizodepressive disorders. The clinical success of risperidone suggests that the development of compounds with selective affinity for 5-HT2 or other serotonin receptors may result in even further improvements in the pharmacotherapy of psychiatric disorders.

Studies on serotonin (5-HT)3-receptor antagonist effects of enantiomers of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives.

We assessed the 5-HT3-receptor antagonist effects of 4,5,6,7-1H-benzimidazole compounds which are derivatives of YM060, a potent and selective 5-HT3-receptor antagonist, in isolated guinea pig colon. YM114 (KAE-393), YM-26103-2, YM-26308-2 (3 x 10(-9) to 3 x 10(-8) M) produced concentration-dependent shifts to the right of the dose-response curves for both 5-HT and 2-methyl-5-HT (2-Me-5-HT). YM114 (pA2 = 9.08 against 5-HT, pA2 = 8.88 against 2-Me-5-HT), YM-26103-2 (pA2 = 8.27 against 5-HT, pA2 = 8.19 against 2-Me-5-HT), and YM-26308-2 (pA2 = 8.58 against 5-HT, pA2 = 8.4 against 2-Me-5-HT) showed similar pA2 values irrespective of the agonist used, suggesting that they have 5-HT3-receptor blocking activity irrespective of the N-position at the aromatic ring. Since these compounds have an asymmetric center, their enantiomers exist. The S-isomers were one to three orders of magnitude less potent than the respective R-isomer compounds, indicating that the stereochemical configuration of 4,5,6,7-tetrahydro-1H-benzimidazoles is an important determinant of their affinity for 5-HT3 receptors. These results suggest that the highly potent 5-HT3 receptor antagonism and high selectivity for 5-HT3 receptors of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives are conserved irrespective of the position of the nitrogen atom in the aromatic ring and that 5-HT3 receptors favor the R-isometric conformation of these compounds.