Una Campbell

The triple reuptake inhibitor DOV216,303 exhibits limited antidepressant-like properties in the differential reinforcement of low-rate 72-second responding assay, likely due to dopamine reuptake inhibition

There is a need for antidepressants with novel mechanisms of action. One approach has been to develop compounds that inhibit reuptake of all three monoamines in the central nervous system, for example DOV216,303. Differential reinforcement of low-rate (72-s) responding is a behavioral test that is predictive of antidepressant-like properties. The effects of antidepressant compounds belonging to multiple classes, the anxiolytic diazepam and the antipsychotic haloperidol, were assessed in the DRL-72s task. Subsequently, the antidepressant-like properties of acute DOV216,303 were assessed. The selective serotonin reuptake inhibitor fluvoxamine, the preferential norepinephrine reuptake inhibitor desipramine and the tricyclic antidepressant imipramine exhibited antidepressant-like properties in the DRL-72s task. The atypical antidepressant bupropion, which inhibits dopamine and norepinephrine reuptake, and the selective dopamine transporter inhibitor GBR12909, changed reinforcement and response rates and inter-response time distribution in an opposite direction compared with the antidepressant compounds tested. The antipsychotic haloperidol exhibited antidepressant-like properties by increasing reinforcement rate, but failed to alter inter-response time distribution. Diazepam did not change reinforcement or response rates or inter-response time distribution. The triple reuptake inhibitor DOV216,303 significantly enhanced reinforcement rate at one intermediate dose, but exhibited similar effects as bupropion and GBR12909 on inter-response time distribution. The studies identified limited antidepressant-like properties of the triple reuptake inhibitor DOV216,303, likely due to dopamine transporter inhibition counteracting the effects of norepinephrine and serotonin transporter inhibition.

Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor

The current work discloses a novel cyclohexylarylamine chemotype with potent inhibition of the serotonin, norepinephrine, and dopamine transporters and potential for treatment of major depressive disorder. Optimized compounds 1 (SERT, NET, DAT, IC(50)=169, 85, 21 nM) and 42 (SERT, NET, DAT IC(50)=34, 295, 90 nM) were highly brain penetrant, active in vivo in the mouse tail suspension test at 30 mpk po and were not general motor stimulants.

Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors.

The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.

Discriminative stimulus properties of GABAA receptor positive allosteric modulators TPA023, ocinaplon and NG2-73 in rats trained to discriminate chlordiazepoxide or zolpidem.

There is increased understanding that distinct GABA(A) receptor subtypes mediate different effects of classical benzodiazepines. Here, we aimed to define the contributions of α(1)-containing subtypes of the subtype-selective GABA(A) receptor positive allosteric modulators TPA023, ocinaplon, and NG2-73 using drug discrimination. We characterized these compounds with defined subunit preferences in rats that were trained to discriminate either the non-selective benzodiazepine chlordiazepoxide (CDP, 5.0 mg/kg) or the α(1)-selective drug zolpidem (1.5 mg/kg). In short, CDP but not zolpidem generalized to the CDP cue. In contrast, zolpidem-trained rats showed opposite effects and generalized to zolpidem but not to CDP, while the response rate reducing effects of both ligands were comparable. Moreover, TPA023, lacking efficacy at the GABA(A) receptor α(1) subunit, occasioned dose-dependent CDP-appropriate responding but generalized only to around 10% to zolpidem. Both ocinaplon and NG2-73 completely generalized to both the CDP and zolpidem cue. Overall, our data confirm and extend the previous findings in rats that compounds that lack efficacy at α(1)-containing GABA(A) receptors generalize to CDP, whereas the opposite holds true for α(1)-preferential compounds, which generalize to the α(1)-selective positive allosteric modulator zolpidem. Also, our data support the hypothesis that subtle in vitro differences in α subunit efficacy and/or affinity may eventually have large consequences in vivo. Together, our data demonstrate a reliable in vivo method to determine the contribution of the subtype-selective mechanism(s) of action for novel and subtype-selective GABA(A) receptor positive allosteric modulators, suggesting that a complex activation of multiple α subunits accounts for drug discrimination between non-selective and selective GABA(A) receptor ligands.

Effects of D-amino acid oxidase inhibition on memory performance and long-term potentiation in vivo.

N‐methyl‐d‐aspartate receptor (NMDAR) activation can initiate changes in synaptic strength, evident as long‐term potentiation (LTP), and is a key molecular correlate of memory formation. Inhibition of d‐amino acid oxidase (DAAO) may increase NMDAR activity by regulating d‐serine concentrations, but which neuronal and behavioral effects are influenced by DAAO inhibition remain elusive. In anesthetized rats, extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded before and after a theta frequency burst stimulation (TBS) of the Schaffer collateral pathway of the CA1 region in the hippocampus. Memory performance was assessed after training with tests of contextual fear conditioning (FC, mice) and novel object recognition (NOR, rats). Oral administration of 3, 10, and 30 mg/kg 4H‐furo[3,2‐b]pyrrole‐5‐carboxylic acid (SUN) produced dose‐related and steady increases of cerebellum d‐serine in rats and mice, indicative of lasting inhibition of central DAAO. SUN administered 2 h prior to training improved contextual fear conditioning in mice and novel object recognition memory in rats when tested 24 h after training. In anesthetized rats, LTP was established proportional to the number of TBS trains. d‐cycloserine (DCS) was used to identify a submaximal level of LTP (5× TBS) that responded to NMDA receptor activation; SUN administered at 10 mg/kg 3–4 h prior to testing similarly increased in vivo LTP levels compared to vehicle control animals. Interestingly, in vivo administration of DCS also increased brain d‐serine concentrations. These results indicate that DAAO inhibition increased NMDAR‐related synaptic plasticity during phases of post training memory consolidation to improve memory performance in hippocampal‐dependent behavioral tests.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

Discovery of 1-(3,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydroquinolin-4-amine, a dual serotonin and dopamine reuptake inhibitor.

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype.

In vivo phenotypic drug discovery: applying a behavioral assay to the discovery and optimization of novel antipsychotic agents

Phenotypic drug discovery (PDD) is increasingly being recognized as a viable compliment to target-based drug discovery (TDD). By measuring functional changes, typically at a systems level, PDD can facilitate the identification of compounds having a desirable pharmacology. This capability is particularly important when studying CNS diseases where drug efficacy may require modulation of multiple targets in order to overcome a robust, adaptive biological system. Here, we report the application of a mouse-based high-dimensional behavioral assay to the discovery and optimization of a structurally and mechanistically novel antipsychotic. Lead optimization focused on optimizing complex behavioral features and no explicit effort was made to identify the target (or targets) involved.