Effect of SMB-1 on K_V7.2-W236L.

<p>(<b>A</b>) Representative current traces for K_V7.2-W236L in the absence and presence of 10 µM SMB-1 (<b>B</b>) Effect of SMB-1 on current-voltage relationship. (<b>C</b>) Effect of SMB-1 on voltage-dependence of activation. (<b>D</b>) Effect of SMB-1 on deactivation kinetics. Statistical significance was determined by paired, two-tailed Student's <i>t</i>-test. Representative tail current traces in the absence and presence of 10 µM SMB-1 are shown in the inset. Effect of SMB-1 on the fast (<b>E</b>) and slow (<b>F</b>) component of the activation kinetics. Statistical significance was determined by two-way repeated measurements ANOVA followed by Bonferroni post-test. Y-values were log-transformed before the statistical analysis to meet the assumption of normality. * <i>p<</i>0.05, ** <i>p<</i>0.01, *** <i>p<</i>0.001. Bars represent S.E.M and <i>n = </i>4–6.</p

Novel Aza-analogous Ergoline Derived Scaffolds as Potent Serotonin 5‑HT₆ and Dopamine D₂ Receptor Ligands.

By introducing distal substituents on a tetracyclic scaffold resembling the ergoline structure, two series of analogues were achieved exhibiting subnanomolar receptor binding affinities for the dopamine D₂ and serotonin 5-HT₆ receptor subtype, respectively. While the 5-HT₆ ligands were antagonists, the D₂ ligands displayed intrinsic activities ranging from full agonism to partial agonism with low intrinsic activity. These structures could potentially be interesting for treatment of neurological diseases such as schizophrenia, Parkinson’s disease, and cognitive deficits

Plasma and brain exposure of SMB-1 in rats following subcutaneous administration of 20 mg/kg.

<p>Data shown as mean total concentrations ± S.E.M (n = 3).</p

Effect of SMB-1 on channels with mutations in the refined retigabine binding site.

<p>Effect of 10 µM SMB-1 on the current-voltage relationship of (A) K_V7.2-L275V, (B) K_V7.2-L299V and (C) K_V7.4-L305V. Bars represent S.E.M. and <i>n = </i>4–6.</p

Inhibition of K_V7.2 by SMB-1.

<p>Chemical structure of (S)-2 (<b>A</b>) and SMB-1 (<b>B</b>). (<b>C</b>) Representative current traces for K_V7.2 in the absence and presence of 10 µM SMB-1 (<b>D</b>) Effect of SMB-1 on current-voltage relationship. (<b>E</b>) Effect of SMB-1 on voltage-dependence of activation. (<b>F</b>) Effect of SMB-1 on deactivation kinetics. Statistical significance was determined by paired, two-tailed Student's <i>t</i>-test. Representative tail current traces in the absence and presence of 10 µM SMB-1 are shown in the inset. Effect of SMB-1 on the fast (<b>G</b>) and slow (<b>H</b>) component of the activation kinetics. Statistical significance was determined by two-way repeated measurements ANOVA followed by Bonferroni post-test. Y-values were log-transformed before the statistical analysis to meet the assumption of normality. (<b>I</b>) Dose-response relationship for the effect of SMB-1 on K_V7.2. *** <i>p<</i>0.001. Bars represent S.E.M and <i>n = </i>5–9. Note that the error bars in some instances are too small to be visible.</p

Activation of K_V7.4 by SMB-1.

<p>(<b>A</b>) Representative current traces for K_V7.4 in the absence and presence of 10 µM SMB-1. (<b>B</b>) Effect of SMB-1 on current-voltage relationship. (<b>C</b>) Effect of SMB-1 on voltage-dependence of activation. (<b>D</b>) Effect of SMB-1 on deactivation kinetics. Statistical significance was determined by paired, two-tailed Student's <i>t</i>-test. Representative tail current traces in the absence and presence of 10 µM SMB-1 are shown in the inset. (<b>E</b>) Effect of SMB-1 on activation kinetics. Statistical significance was determined by two-way repeated measurements ANOVA followed by Bonferroni post-test. (<b>F</b>) Dose-response relationship of SMB-1 on K_V7.4. *** <i>p<</i>0.001. Bars represent S.E.M and <i>n = </i>5–8.</p

Effect of SMB-1 on K_V7.4-W242L.

<p>(<b>A</b>) Representative current traces for K_V7.4-W242L in the absence and presence of 10 µM SMB-1. (<b>B</b>) Effect of SMB-1 on current-voltage relationship. (<b>C</b>) Effect of SMB-1 on voltage-dependence of activation. (<b>D</b>) Effect of SMB-1 on deactivation kinetics. Statistical significance was determined by paired, two-tailed Student's <i>t</i>-test. Representative tail current traces in the absence and presence of 10 µM SMB-1 are shown in the inset (note that the traces are completely overlapping). (<b>E</b>) Effect of SMB-1 on activation kinetics. Statistical significance was determined by two-way repeated measurements ANOVA followed by Bonferroni post-test. Bars represent S.E.M and <i>n = </i>5.</p

Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia

Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in Lister Hooded rats treated with the PDE1B inhibitor Lu AF64386 and tested in the 5-choice serial reaction time task (5-CSRTT). We also asked whether PDE1B inhibition modulates neurophysiological deficits produced by subchronic phencyclidine (PCP) treatment, a rat pharmacological model of schizophrenia. Lu AF64386 significantly affected behavioural parameters consistent with a reduction in goal-directed behaviour, however without affecting accuracy. Additionally, it reduced mPFC neuronal activity. Pre-treatment with PCP did not affect behavioural parameters, however it significantly disrupted overall neuronal firing while increasing phasic responses to reward-predicting cues and disrupting mPFC-NAc cross-talk. The latter two effects were reversed by Lu AF64386. These findings suggest PDE1B inhibition may be beneficial in disorders implicating a dysfunction of the mPFC-NAc network

5‑HT_2A/5-HT_2C Receptor Pharmacology and Intrinsic Clearance of <i>N</i>‑Benzylphenethylamines Modified at the Primary Site of Metabolism

The toxic hallucinogen 25B-NBOMe is very rapidly degraded by human liver microsomes and has low oral bioavailability. Herein we report on the synthesis, microsomal stability, and 5-HT_2A/5-HT_2C receptor profile of novel analogues of 25B-NBOMe modified at the primary site of metabolism. Although microsomal stability could be increased while maintaining potent 5-HT₂ receptor agonist properties, all analogues had an intrinsic clearance above 1.3 L/kg/h predictive of high first-pass metabolism

Synthesis and Biological Evaluation of 4‑(Aminomethyl)-1-hydroxypyrazole Analogues of Muscimol as γ‑Aminobutyric Acid_A Receptor Agonists

A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole (4-AHP) analogues of muscimol, a GABA_A receptor agonist, has been synthesized and pharmacologically characterized at native and selected recombinant GABA_A receptors. The unsubstituted 4-AHP analogue (<b>2a</b>) (EC₅₀ 19 μM, <i>R</i>_max 69%) was a moderately potent agonist at human α₁β₂γ₂ GABA_A receptors, and in SAR studies substitutions in the 3- and/or 5-position were found to be detrimental to binding affinities. Ligand–receptor docking in an α₁β₂γ₂ GABA_A receptor homology model along with the obtained SAR indicate that <b>2a</b> and muscimol share a common binding mode, which deviates from the binding mode of the structurally related antagonist series based on 4-(piperidin-4-yl)-1-hydroxypyrazole (4-PHP, <b>1</b>). Selectivity for α₁β₂γ₂ over ρ₁ GABA_A receptors was observed for the 5-chloro, 5-bromo, and 5-methyl substituted analogues of <b>2a</b> illustrating that even small differences in structure can give rise to subtype selectivity