SLV313 is a dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist: In vitro and in vivo neuropharmacology

Glennon, Jeffrey C.; McCreary, Andrew C.; Ronken, Eric; Siarey, Richard J.; Hesselink, Mayke B.; Feenstra, Rolf W.; Vliet, B. Van; Long, Sihui; Kruse, C.G.

doi:10.1016/s0924-977x(02)80381-9

Cited by 8 publications

(5 citation statements)

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“…In contrast, SLV313 exhibits balanced 5-HT 1A / D 2 affinity and intermediate efficacy at 5-HT 1A receptors, but little interaction with D 1 , 5-HT 2A or a 1/2 adrenergic receptors (Newman-Tancredi et al, 2005; Assié MB, unpublished observations). SLV313 blocks psychostimulant-induced behaviors in rodents in the absence of catalepsy; of the compounds tested here SLV313 had the highest antipsychotic-like vs catalepsy separation (present data; Glennon et al, 2002;Kleven et al, 2005) suggesting that its balance of 5-HT 1A /D 2 properties produces a favorable antipsychotic profile. In contrast, SLV314, another 'selectively nonselective' 5-HT 1A agonist/D 2 antagonist (Roth et al, 2004), exhibits affinity at 5-HT 1A receptors that is two orders of magnitude lower than that of D 2 receptors and its cataleptogenic liability is higher than that of SLV313 (ED 50 ¼ 0.5 vs 440 mg/kg).…”

Section: Antipsychotic Activity Of the New Generation Of Antipsychotimentioning

confidence: 57%

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Bardin

Kleven

Barret-Grévoz

et al. 2005

Neuropsychopharmacol

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A new generation of proven or potential antipsychotics, including aripiprazole, bifeprunox, SSR181507 and SLV313, exhibit agonist actions at serotonin 5-HT 1A receptors, but little comparative data are available on their pharmacological profiles. Here, we compared in mice the in vivo antipsychotic-like vs cataleptogenic activities of these compounds with those of drugs that exhibit little interaction at 5-HT 1A receptors, such as haloperidol, olanzapine and risperidone. All the drugs dose-dependently reduced apomorphine-induced climbing or sniffing and, with the exception of ziprasidone, produced complete suppression of these responses. In the bar catalepsy test, when administered alone, haloperidol, olanzapine and risperidone produced marked catalepsy, whereas, at doses up to 40 mg/kg, aripiprazole, SLV313, SSR181507, and sarizotan produced little or no catalepsy. The latter compounds, therefore, displayed a large separation between doses with 'antipsychotic-like' and those with cataleptogenic actions. When 5-HT 1A receptors were blocked by pretreatment with WAY100635 (2.5 mg/kg, s.c.), cataleptogenic properties of SSR181507 and sarizotan were unmasked, and the catalepsy induced by bifeprunox was enhanced. In the case of aripiprazole and SLV313, although WAY100635 produced upward shifts in their dose-response, the magnitude of catalepsy appeared to reach an asymptotic plateau, suggesting that other mechanisms may be involved in their low cataleptogenic liability. The present data confirm that 5-HT 1A receptor activation reduces or even completely prevents the cataleptogenic potential of novel antipsychotic agents. Further, they indicate that the balance of affinity and/or efficacy between D 2 and 5-HT 1A receptors profoundly influences their pharmacological activities, and will likely impact their therapeutic profiles.

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Section: Antipsychotic Activity Of the New Generation Of Antipsychotimentioning

confidence: 57%

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Bardin

Kleven

Barret-Grévoz

et al. 2005

Neuropsychopharmacol

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“…This is a particularly relevant issue in view of the increasing attention devoted to novel commercialized or putative antipsychotics with combined D 2 /5-HT 1A activities including aripiprazole, bifeprunox, SLV313, SSR181507 and F15063 (Van Vliet et al, 2000;Glennon et al, 2002;McCreary et al, 2002;Claustre et al, 2003;Shapiro et al, 2003;Wolf, 2003;Depoortere et al, 2007a, b;Newman-Tancredi et al, 2007). This is a particularly relevant issue in view of the increasing attention devoted to novel commercialized or putative antipsychotics with combined D 2 /5-HT 1A activities including aripiprazole, bifeprunox, SLV313, SSR181507 and F15063 (Van Vliet et al, 2000;Glennon et al, 2002;McCreary et al, 2002;Claustre et al, 2003;Shapiro et al, 2003;Wolf, 2003;Depoortere et al, 2007a, b;Newman-Tancredi et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice

Slot¹,

Bardin

Auclair

et al. 2008

Behavioural Pharmacology

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Antipsychotics constitute efficacious augmenting agents in the treatment of anxiety disorders, including refractory obsessive-compulsive disorder. We examined the effects of 36 compounds, including typical, atypical and novel antipsychotics with dual dopamine D2/5-hydroxytryptamine 1A (D2/5-HT1A) actions on marble burying behavior in mice, a putative preclinical test for anxiety disorders. One hour after drug administration, male NMRI mice were placed individually in cages containing 20 marbles, and the total number of marbles buried after 30 min was counted. The selective serotonin reuptake inhibitors, citalopram (2.5-40 mg/kg), fluoxetine (2.5-10 mg/kg) and the benzodiazepine diazepam (2.5-10 mg/kg), reduced the number of buried marbles. The atypical antipsychotic, clozapine (0.16-10 mg/kg), but not its congener olanzapine, was effective in this test. Haloperidol, a typical antipsychotic, also reduced the number of buried marbles, albeit not in a dose-dependent manner. The atypical risperidone was partially active (0.16-0.63 mg/kg), as was the benzamide derivative, amisulpride, albeit at high (10-40 mg/kg) doses. Among the 'third-generation' antipsychotics possessing combined D2/5-HT1A properties, bifeprunox was active at 0.0025 mg/kg, whereas SLV313 and aripiprazole were active only at the highest doses (2.5 and 10 mg/kg, respectively). SSR181507, F15063 and the antidyskinetic agent, sarizotan, were without any effect. Among a series of receptor subtype-selective ligands, only the 5-HT1A agonist, (+)-8-OH-DPAT (0.63-2.5 mg/kg) and the 5-HT2A/2B/2C antagonist, ritanserin (0.63-2.5 mg/kg) were active. Among novel antipsychotics with dual D2/5-HT1A properties, only bifeprunox was able to potently reduce the number of buried marbles. Inhibition of marble burying behavior may result from the interplay of several receptor systems, including 5-HT2 receptor blockade, dopamine D2 partial agonism and serotonin 5-HT1A agonism.

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“…As well as clozapine -ziprasidone and nemonapride exhibit partial agonist properties at 5-HT1A receptors, as do aripiprazole and bifeprunox, which are recently commercialized and in late-stage development respectively (Jordan et al, 2002b(Jordan et al, , 2004Van Vliet et al, 2000a,b). Further, a new generation of potential antipsychotic agents in early clinical development, such as SSR181507 and SLV313, is specifically targeted at 5-HT1A receptors, in addition to dopamine receptors (Claustre et al, 2003 ;Depoortere et al, 2003 ;Feenstra et al, 2002 ;Glennon et al, 2002). Sarizotan (EMD128907), another compound with potent 5-HT1A agonist properties (Bartoszyk et al, 2004), was also initially in development as an antipsychotic.…”

Section: Introductionmentioning

confidence: 99%

Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia

Newman‐Tancredi

Assié

Leduc

et al. 2005

Int. J. Neuropsychopharm.

123

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Serotonin 5-HT1A receptors are promising targets in the management of schizophrenia but little information exists about affinity and efficacy of novel antipsychotics at these sites. We addressed this issue by comparing binding affinity at 5-HT1A receptors with dopamine rD2 receptors, which are important targets for antipsychotic drug action. Agonist efficacy at 5-HT1A receptors was determined for G-protein activation and adenylyl cyclase activity. Whereas haloperidol, thioridazine, risperidone and olanzapine did not interact with 5-HT1A receptors, other antipsychotic agents exhibited agonist properties at these sites. E(max) values (% effect induced by 10 microM of 5-HT) for G-protein activation at rat brain 5-HT1A receptors: sarizotan (66.5), bifeprunox (35.9), SSR181507 (25.8), nemonapride (25.7), ziprasidone (20.6), SLV313 (19), aripiprazole (15), tiospirone (8.9). These data were highly correlated with results obtained at recombinant human 5-HT1A receptors in determinations of G-protein activation and inhibition of forskolin-stimulated adenylyl cyclase. In binding-affinity determinations, the antipsychotics exhibited diverse properties at r5-HT1A receptors: sarizotan (pK(i)=8.65), SLV313 (8.64), SSR181507 (8.53), nemonapride (8.35), ziprasidone (8.30), tiospirone (8.22), aripiprazole (7.42), bifeprunox (7.19) and clozapine (6.31). The affinity ratios of the ligands at 5-HT1A vs. D2 receptors also varied widely: ziprasidone, SSR181507 and SLV313 had similar affinities whereas aripiprazole, nemonapride and bifeprunox were more potent at D2 than 5-HT1A receptors. Taken together, these data indicate that aripiprazole has low efficacy and modest affinity at 5-HT1A receptors, whereas bifeprunox has low affinity but high efficacy. In contrast, SSR181507 has intermediate efficacy but high affinity, and is likely to have more prominent 5-HT1A receptor agonist properties. Thus, the contribution of 5-HT1A receptor activation to the pharmacological profile of action of the antipsychotics will depend on the relative 5-HT1A/D2 affinities and on 5-HT1A agonist efficacy of the drugs.

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SLV313 is a dopamine D2 receptor antagonist and serotonin 5-HT1A receptor agonist: In vitro and in vivo neuropharmacology

Cited by 8 publications

References 0 publications

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Antipsychotic-Like vs Cataleptogenic Actions in Mice of Novel Antipsychotics Having D2 Antagonist and 5-HT1A Agonist Properties

Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice

Novel antipsychotics activate recombinant human and native rat serotonin 5-HT1A receptors: affinity, efficacy and potential implications for treatment of schizophrenia

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