3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine:  An Antagonist with High Affinity and Selectivity for the Human Dopamine D4 Receptor

Kulagowski, Janusz J.; Broughton, Howard B.; Curtis, Neil R.; Mawer, Ian M.; Ridgill, Mark P.; Baker, Raymond; Emms, Frances; Freedman, Stephen B.; Marwood, Rosemarie; Patel, Shil; Patel, Smita S.; Ragan, C I; Leeson, Paul D.

doi:10.1021/jm9600712

Cited by 242 publications

(137 citation statements)

References 17 publications

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“…1 and 2). To address the impact of D2-like DA receptors on the production of DA neurons from hESCs the expanding neuroepithelial rosettes were treated with D2-antagonist L741 [36] late in the protocol, when TH protein is expressed (Fig. 2).…”

Section: Selective D2-like Da Receptor Inhibitionmentioning

confidence: 99%

“…The insertion of sodium channels in developing human neurons is manifested in electrophysiological recordings by an increase in peak amplitude of the fast inactivating sodium current paralleled by neuronal ability to generate APs [28]. In the current project, whole cell recordings were performed on differentiated cells at Stage 5 (days [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], after at least 2 weeks of chronic DA exposure. Each cell was typically recorded in 2 electrical configurations; current clamp for assessing the voltage waveforms of APs (Fig.…”

Section: Physiological Properties After Da Treatmentmentioning

confidence: 99%

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Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Belinsky

Sirois

Rich

et al. 2013

Stem Cells and Development

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We tested whether dopaminergic drugs can improve the protocol for in vitro differentiation of H9 human embryonic stem cells (hESCs) into dopaminergic neurons. The expression of 5 dopamine (DA) receptor subtypes (mRNA and protein) was analyzed at each protocol stage (1, undifferentiated hESCs; 2, embryoid bodies [EBs]; 3, neuroepithelial rosettes; 4, expanding neuroepithelium; and 5, differentiating neurons) and compared to human fetal brain (gestational week 17-19). D2-like DA receptors (D2, D3, and D4) predominate over the D1-like receptors (D1 and D5) during derivation of neurons from hESCs. D1 was the receptor subtype with the lowest representation in each protocol stage (Stages 1-5). D1/D5-agonist SKF38393 and D2/D3/D4-agonist quinpirole (either alone or combined) evoked Ca 2 + responses, indicating functional receptors in hESCs. To identify when receptor activation causes a striking effect on hESC neurodifferentiation, and what ligands and endpoints are most interesting, we varied the timing, duration, and drug in the culture media. Dopaminergic agonists or antagonists were administered either early (Stages 1-3) or late (Stages 4-5). Early DA exposure resulted in more neuroepithelial colonies, more neuronal clusters, and more TH + clusters. The D1/D5 antagonist SKF83566 had a strong effect on EB morphology and the expression of midbrain markers. Late exposure to DA resulted in a modest increase in TH + neuron clusters (*75%). The increase caused by DA did not occur in the presence of dibutyryl cAMP (dbcAMP), suggesting that DA acts through the cAMP pathway. However, a D2-antagonist (L741) decreased TH + cluster counts. Electrophysiological parameters of the postmitotic neurons were not significantly affected by late DA treatment (Stages 4-5). The mRNA of mature neurons (VGLUT1 and GAD1) and the midbrain markers (GIRK2, LMX1A, and MSX1) were lower in hESCs treated by DA or a D2-antagonist. When hESCs were neurodifferentiated on PA6 stromal cells, DA also increased expression of tyrosine hydroxylase. Although these results are consistent with DA's role in potentiating DA neurodifferentiation, dopaminergic treatments are generally less efficient than dbcAMP alone.

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Section: Selective D2-like Da Receptor Inhibitionmentioning

confidence: 99%

Section: Physiological Properties After Da Treatmentmentioning

confidence: 99%

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Belinsky

Sirois

Rich

et al. 2013

Stem Cells and Development

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“…To verify that D 4 receptors were mediating the modulation seen with PD168077, we examined the ability of L-745870, a highly selective D 4 antagonist (Kulagowski et al, 1996;Patel et al, 1997), to prevent the action of PD168077. Dissociated neurons were treated with L-745870 for 15 min before the examination of the PD168077 effect.…”

Section: Activation Of D 4 Receptors Reduces Gaba a Receptor Currentsmentioning

confidence: 99%

Dopamine D₄Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

2002

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The D 4 modulation of GABA A receptor currents was blocked by protein kinase A (PKA) activation and occluded by PKA inhibition. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of PD168077 on GABA A currents. Furthermore, disrupting the association of the PKA/PP1 complex with its scaffold protein Yotiao significantly attenuated the D 4 modulation of GABA A currents, suggesting that Yotiao-mediated targeting of PKA/PP1 to the vicinity of GABA A receptors is required for the dopaminergic signaling. Together, our results show that activation of D 4 receptors in PFC pyramidal neurons inhibits GABA A channel functions by regulating the PKA/PP1 signaling complex, which could underlie the D 4 modulation of PFC neuronal activity and the actions of antipsychotic drugs.

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“…Here we report for the first time that some of the most commonly used dopamine D 4 receptor selective antagonists, L745,870, L741,741 and RBI-257, have nanomolar affinities for the cloned sigma 1 receptor, with the latter two having very high affinities that are within 10-fold of that reported for D 4 receptors (Kulagowski et al, 1996;Rowley et al, 1996;Kula et al, 1999). In contrast, the dopamine D 4 receptor selective agonist PD168,077 (Glase et al, 1997) and antagonist NGD 94-1 (Tallman et al, 1997) have micromolar affinities for the sigma 1 receptor.…”

Section: Discussionmentioning

confidence: 62%

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

Lee

Chen

Schetz

2008

European Journal of Pharmacology

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The ability of sigma 1 receptors to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma 1 receptor ligands vary more than 50-fold. The potential of the sigma 1 receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma 1 receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D 4 receptor selective compounds bind sigma 1 receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with sigma 1 receptor were confirmed with our screening assay.

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3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine: An Antagonist with High Affinity and Selectivity for the Human Dopamine D₄ Receptor

Cited by 242 publications

References 17 publications

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Dopamine D₄Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

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3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine: An Antagonist with High Affinity and Selectivity for the Human Dopamine D4 Receptor

Cited by 242 publications

References 17 publications

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Dopamine Receptors in Human Embryonic Stem Cell Neurodifferentiation

Dopamine D4Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

Contact Info

Product

Resources

About

3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine: An Antagonist with High Affinity and Selectivity for the Human Dopamine D₄ Receptor

Dopamine D₄Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex