11 research outputs found
Effect of SMB-1 on K<sub>V</sub>7.2-W236L.
<p>(<b>A</b>) Representative current traces for K<sub>V</sub>7.2-W236L in the absence and presence of 10 ”M 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 ”M 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>nâ=â</i>4â6.</p
Novel Aza-analogous Ergoline Derived Scaffolds as Potent Serotonin 5âHT<sub>6</sub> and Dopamine D<sub>2</sub> 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 D<sub>2</sub> and serotonin 5-HT<sub>6</sub> receptor subtype, respectively. While
the 5-HT<sub>6</sub> ligands were antagonists, the D<sub>2</sub> 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,
Parkinsonâs 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 (nâ=â3).</p
Effect of SMB-1 on channels with mutations in the refined retigabine binding site.
<p>Effect of 10 ”M SMB-1 on the current-voltage relationship of (A) K<sub>V</sub>7.2-L275V, (B) K<sub>V</sub>7.2-L299V and (C) K<sub>V</sub>7.4-L305V. Bars represent S.E.M. and <i>nâ=â</i>4â6.</p
Inhibition of K<sub>V</sub>7.2 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<sub>V</sub>7.2 in the absence and presence of 10 ”M 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 ”M 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<sub>V</sub>7.2. *** <i>p<</i>0.001. Bars represent S.E.M and <i>nâ=â</i>5â9. Note that the error bars in some instances are too small to be visible.</p
Activation of K<sub>V</sub>7.4 by SMB-1.
<p>(<b>A</b>) Representative current traces for K<sub>V</sub>7.4 in the absence and presence of 10 ”M 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 ”M 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<sub>V</sub>7.4. *** <i>p<</i>0.001. Bars represent S.E.M and <i>nâ=â</i>5â8.</p
Effect of SMB-1 on K<sub>V</sub>7.4-W242L.
<p>(<b>A</b>) Representative current traces for K<sub>V</sub>7.4-W242L in the absence and presence of 10 ”M 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 ”M 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>nâ=â</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
5âHT<sub>2A</sub>/5-HT<sub>2C</sub> Receptor Pharmacology and Intrinsic Clearance of <i>N</i>âBenzylphenethylamines 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<sub>2A</sub>/5-HT<sub>2C</sub> 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-HT<sub>2</sub> 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 4â(Aminomethyl)-1-hydroxypyrazole Analogues of Muscimol as ÎłâAminobutyric Acid<sub>A</sub> Receptor Agonists
A series of bioisosteric 4-(aminomethyl)-1-hydroxypyrazole
(4-AHP)
analogues of muscimol, a GABA<sub>A</sub> receptor agonist, has been
synthesized and pharmacologically characterized at native and selected
recombinant GABA<sub>A</sub> receptors. The unsubstituted 4-AHP analogue
(<b>2a</b>) (EC<sub>50</sub> 19 ÎŒM, <i>R</i><sub>max</sub> 69%) was a moderately potent agonist at human α<sub>1</sub>ÎČ<sub>2</sub>Îł<sub>2</sub> GABA<sub>A</sub> receptors,
and in SAR studies substitutions in the 3- and/or 5-position were
found to be detrimental to binding affinities. Ligandâreceptor
docking in an α<sub>1</sub>ÎČ<sub>2</sub>Îł<sub>2</sub> GABA<sub>A</sub> 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 α<sub>1</sub>ÎČ<sub>2</sub>Îł<sub>2</sub> over Ï<sub>1</sub> GABA<sub>A</sub> 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