SLV313: A novel antipsychotic with additional antidepressant and anxiolytic-like actions

McCreary, Andrew C.; Glennon, Jeffrey C.; Tuinstra, T.; Herremans, Arnoud H.J.; Heyden, J.A.M. van der; Feenstra, Rolf W.; Long, Sihui; Kruse, Chris G.

doi:10.1016/s0924-977x(02)80374-1

Cited by 14 publications

(10 citation statements)

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“…Nonetheless, it seems that overall, its 5-HT 1A receptor agonist activity predominates. It should be noted, however, that in the only other study (in an abstract form) published on SLV313, it was reported that the compound could attenuate effect of PPI disruption at doses less than 0.1 mg/kg (McCreary et al, 2002). The reasons for this discrepancy between this study and ours are not clear at the moment.…”

Section: Discussioncontrasting

confidence: 89%

“…Here again, it can be considered that the compound preferentially activates 5-HT 1A receptors, hence its lack of activity against apomorphine-induced PPI impairment. The case for SLV313 is slightly different: despite the fact that it had even more moderate efficacy at 5-HT 1A receptors (28% that of ( + )8-OH-DPAT), its rKi was also close to unity (0.9: Newman-Tancredi et al, 2005) but it behaved as a DA D 2 receptor antagonist McCreary et al, 2002;Cosi et al, in press). Nonetheless, it seems that overall, its 5-HT 1A receptor agonist activity predominates.…”

Section: Discussionmentioning

confidence: 99%

“…These considerations have led to the development of compounds with preferential DA D 2 receptor antagonist or partial agonist, and 5-HT 1A agonist activities, such as bifeprunox (Feenstra et al, 2001;Wolf, 2003), SSR181507 (Claustre et al, 2003;Depoortere et al, 2003;Boulay et al, 2004), SLV313 McCreary et al, 2002), and sarizotan (that has been re-oriented towards an antidyskinetic indication: Bibbiani et al, 2001;Rabiner et al, 2002;Bartoszyk et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Auclair

Kleven

Besnard

et al. 2006

Neuropsychopharmacol

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The dopamine D1/D2 agonist apomorphine (0.63 mg/kg) disrupted prepulse inhibition (PPI) of acoustic startle in rats, a model of sensorimotor gating deficits observed in schizophrenia. All current antipsychotics, which antagonize D 2 receptors, prevent this apomorphine-induced deficit. A novel class of antipsychotics possesses, in addition to D 2 antagonist property, various levels of 5-HT 1A agonist activity. Considering that the latter itself produces PPI deficits, it appeared necessary to assess the potential of this novel class of antipsychotics to reverse apomorphine-PPI deficits. Potent D 2 antagonists, like haloperidol (0.63-2.5 mg/kg), risperidone (0.63-10 mg/kg), and olanzapine (0.63-40 mg/kg) prevented apomorphine PPI disruption. The atypical antipsychotics, clozapine (40 mg/kg), nemonapride (0.01-2.5 mg/kg), ziprasidone (10 mg/kg), and aripiprazole (0.01 and 10 mg/kg), which all exhibit 5-HT 1A agonist properties, reversed PPI deficits at some doses only, whereas the anti-dyskinetic agent sarizotan (0.16-10 mg/kg), an efficacious 5-HT 1A agonist, did not. New generation antipsychotics with marked 5-HT 1A agonist properties, such as SLV313 and SSR181507 (0.0025-10 mg/kg and 0.16-10 mg/kg, respectively) did not reverse these deficits whereas bifeprunox (0.04-2.5 mg/kg) did. To reveal the contribution of 5-HT 1A agonist properties in the lack of effects of SLV313 and SSR181507, we pretreated rats with the 5-HT 1A antagonist WAY100635 (0.63 mg/kg). Under these conditions, significant reversal of PPI deficit was observed, indicating that D 2 antagonist properties of SLV313 and SSR181507 are now sufficient to overcome the disruptive effects of apomorphine. To summarize, antipsychotics possessing agonist efficacy at 5-HT 1A receptors exhibit diverse profiles against apomorphine-induced PPI deficits, depending on the balance between D 2 and 5-HT 1A activities, suggesting that they may display distinct activity on some aspects of gating deficits in schizophrenic patients.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Auclair

Kleven

Besnard

et al. 2006

Neuropsychopharmacol

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“…For example, the potentiation of antipsychotic-like effects in the CAR paradigm (Wadenberg and Ahlenius, 1991;Prinssen et al, 1996) at doses far lower than the 'normal' cataleptic dose and the effects seen with SLV313 in the CAR paradigm (McCreary et al, 2002) support potential efficacy against the positive symptoms of schizophrenia, but positive symptoms are not the only symptom set in schizophrenia. One of the hypotheses of the abnormalities underlying schizophrenia has been the hypofrontality model which proposes hypoactive mPFCx circuitry in schizophrenia (Weinberger and Lipska, 1995).…”

Section: Discussionmentioning

confidence: 99%

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

McCreary

Glennon

Ashby

et al. 2006

Neuropsychopharmacol

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Combined dopamine D 2 receptor antagonism and serotonin (5-HT) 1A receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D 2/3 antagonist and 5-HT 1A agonist. SLV313 possessed high affinity at human recombinant D 2 , D 3 , D 4 , 5-HT 2B , and 5-HT 1A receptors, moderate affinity at 5-HT 7 and weak affinity at 5-HT 2A receptors, with little-no affinity at 5-HT 4 , 5-HT 6 , a 1 , and a 2 (rat), H 1 (guinea pig), M 1 , M 4 , 5-HT 3 receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT 1A receptors (pEC 50 ¼ 9.0) and full antagonist activity at hD 2 (pA 2 ¼ 9.3) and hD 3 (pA 2 ¼ 8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT 1A syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT 1A antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT 1A -dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT 1A receptor agonist and full D 2/3 receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia. Neuropsychopharmacology (2007) 32, 78-94.

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“…5-HT 1A receptor activation also increases DA release in prefrontal cortex (Rollema et al 1997(Rollema et al , 2000Millan et al 1998;Ichikawa et al 2001), indicative of beneficial activity against negative symptomatology and cognitive disturbances of schizophrenia (Kapur and Remington 1996). These considerations have led to the development of compounds with preferential DA D 2 receptor antagonist/partial agonist and 5-HT 1A agonist activities such as bifeprunox (Feenstra et al 2001;Wolf 2003), SSR181507 (Claustre et al 2003;Depoortere et al 2003;Boulay et al 2004;Terranova et al 2005), SLV313 McCreary et al 2002), and sarizotan (now developed as an anti-dyskinetic: Bibbiani et al 2001;Rabiner et al 2002;Bartoszyk et al 2004). …”

Section: Introductionmentioning

confidence: 99%

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats

et al. 2007

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SLV313: A novel antipsychotic with additional antidepressant and anxiolytic-like actions

Cited by 14 publications

References 0 publications

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

Actions of Novel Antipsychotic Agents on Apomorphine-Induced PPI Disruption: Influence of Combined Serotonin 5-HT1A Receptor Activation and Dopamine D2 Receptor Blockade

SLV313 (1-(2,3-Dihydro-Benzo[1,4]Dioxin-5-yl)-4- [5-(4-Fluoro-Phenyl)-Pyridin-3-ylmethyl]-Piperazine Monohydrochloride): A Novel Dopamine D2 Receptor Antagonist and 5-HT1A Receptor Agonist Potential Antipsychotic Drug

Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats

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