SONU20176289, a compound combining partial dopamine D(2) receptor agonism with specific serotonin reuptake inhibitor activity, affects neuroplasticity in an animal model for depression.

We investigated the efficacy of SONU20176289, a member of a group of novel phenylpiperazine derivatives with a mixed dopamine D(2) receptor partial agonist and specific serotonin reuptake inhibitor (SSRI) activity, in a chronic stress model of depression in male tree shrews. Animals were subjected to a 7-day period of psychosocial stress before treatment for 28 days with SONU20176289 (6 mg/kg/day, p.o.), during which stress was maintained. Stress reduced the in vivo brain concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds, as measured by localized proton magnetic resonance spectroscopy. Post mortem analyses revealed a reduced adult dentate cell proliferation and a decreased GluR2 expression in the prefrontal cortex. All these alterations were prevented by concomitant administration of SONU20176289. The results provide further support to the concept that antidepressant treatments may act by normalizing disturbed neuroplasticity, and indicate that combining dopamine D(2) receptor agonism with SSRI activity may serve as an effective tool in the treatment of depressive/anxiety syndromes.

Multi-modal characterisation of the neocortical clip model of focal cerebral ischaemia by MRI, behaviour and immunohistochemistry.

The neocortical clip model of focal cerebral ischaemia has previously been used with success in neuroprotection studies. To further improve its translational qualities, we have characterised this model using a combination of serial Magnetic Resonance Imaging (MRI), neurological assessment, the bilateral asymmetry test (BAT) and immunohistochemistry. The right MCA was occluded in spontaneously hypertensive rats for 0, 60 and 120 min. MRI was performed pre-surgery, 1, 3 and 7 days post-surgery. Behavioural assessment was performed 2 days before and 3 and 7 days post-surgery whilst neurological deficits were monitored daily. Neuroimaging results showed that 0 min of MCA occlusion did not produce a lesion, whereas occlusion for 60 min produced a lesion that remained stable over time. Occlusion for 120 min caused a more severe lesion 1 day post-surgery, but decreased by 7 days. Behaviour, neurological scores and histological lesion volumes correlated strongly with MRI lesion volume. Immunohistochemistry revealed neuronal loss, astrogliosis and macrophage infiltration in lesioned cortices. The neocortical clip model produced ischaemic lesions that are restricted to cortical territories of the MCA. The duration of occlusion dictates lesion severity which may prove useful for probing therapeutic interventions at different stages of stroke progression. The correlation of MRI with two different behavioural measures and post-mortem histology strengthens the basis for MRI providing an in vivo surrogate marker for structural and behavioural deficits caused by a cortical stroke.

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.

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-dihydro-benzo[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), alpha(1), and alpha(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)=9.0) and full antagonist activity at hD(2) (pA(2)=9.3) and hD(3) (pA(2)=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.

In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist.

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.

Synthesis, structure-activity relationships, and biological properties of 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines, novel potential antipsychotics combining potent dopamine D2 receptor antagonism with potent serotonin reuptake inhibition.

A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.

Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist.

Previous studies have demonstrated that stress may affect the hippocampal GABAergic system. Here, we examined whether long-term psychosocial stress influenced the number of parvalbumin-containing GABAergic cells, known to provide the most powerful inhibitory input to the perisomatic region of principal cells. Adult male tree shrews were submitted to 5 weeks of stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number of hippocampal parvalbumin-immunoreactive (PV-IR) neurons. Stress significantly decreased the number of PV-IR cells in the dentate gyrus (DG) (-33%), CA2 (-28%), and CA3 (-29%), whereas the CA1 was not affected. Additionally, we examined whether antidepressant treatment offered protection from this stress-induced effect. We administered fluoxetine (15 mg/kg per day) and SLV-323 (20 mg/kg per day), a novel neurokinin 1 receptor (NK1R) antagonist, because the NK1R has been proposed as a possible target for novel antidepressant therapies. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of the drugs, with stress continued throughout the 28-day treatment period. NK1R antagonist administration completely prevented the stress-induced reduction of the number of PV-IR interneurons, whereas fluoxetine attenuated this decrement in the DG, without affecting the CA2 and CA3. The effect of stress on interneuron numbers may reflect real cell loss; alternatively, parvalbumin concentration is diminished in the neurons, which might indicate a compensatory attempt. In either case, antidepressant treatment offered protection from the effect of stress and appears to modulate the hippocampal GABAergic system. Furthermore, the NK1R antagonist SLV-323 showed neurobiological efficacy similar to that of fluoxetine.

Tonic inhibition by orphanin FQ/nociceptin of noradrenaline neurotransmission in the amygdala.

The present microdialysis study investigated whether nociceptin/orphanin FQ exerts a tonic inhibition of the release of noradrenaline in the basolateral nucleus of the amygdala in awake rats. The non-peptide competitive nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist J-113397 (20 mg/kg i.p.) induced an increase in the release of noradrenaline to about 150-200%. The increase was strongly suppressed by local infusion of an endogenous N/OFQ peptide receptor agonist, nociceptin/orphanin FQ (1 microM) via retrograde microdialysis, into the basolateral nucleus of the amygdala. Local infusion of nociceptin/orphanin FQ (1 microM) itself reduced noradrenaline release in the basolateral nucleus of the amygdala to about 70% of basal levels. These results indicate that a large part of basal release of noradrenaline in the basolateral nucleus of the amygdala is under tonic inhibitory control by endogenous nociceptin/orphanin FQ through the N/OFQ peptide receptors localized within the basolateral nucleus of the amygdala.

SLV310, a novel, potential antipsychotic, combining potent dopamine D2 receptor antagonism with serotonin reuptake inhibition.

In this paper, SLV310 is presented as a novel, potential antipsychotic displaying the interesting combination of potent dopamine D(2) receptor antagonism and serotonin reuptake receptor inhibition in one molecule. As such, SLV310 could be useful in treating a broad range of symptoms in schizophrenia. This paper describes the structure-activity relationship in a series of compounds leading to SLV310 (6b, 2-[4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl]-phthalimide) together with pharmacological data showing the unique profile of this compound.