Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor

Schlachter, S. K.; Poel, Toni J.; Lawson, Charles; Dinh, Dac M.; Lajiness, Mary E.; Romero, Arthur G.; Rees, Susan A; Duncan, J. Neil; Smith, Martin

doi:10.1016/s0014-2999(97)00013-7

Cited by 30 publications

(17 citation statements)

References 13 publications

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“…These findings, however, were not confirmed by other studies using similar functional assays Schlachter et al 1997). We recently reported that motor hyperactivity induced by neonatal 6-OHDA lesions in rats was inhibited by the D 4 antagonist CP-293,019, and exacerbated by the D 4 agonist CP-226,269.…”

Section: Discussioncontrasting

confidence: 62%

“…n=10/group CP-293,019 (Zhang et al 2001b), but not S-18126 (Figs 3, 4 and 5). All three agents tested in the present study are D 4 receptor-selective antagonists with high affinity for D 4 receptors (K i =0.4, 2.7, and 2.4 nM, respectively), and much lower affinity for D 2 receptors (all K i >700 nM) Schlachter et al 1997;Millan et al 1998). …”

Section: Discussionmentioning

confidence: 55%

“…1) were examined and compared to that of ketanserin, a 5-HT 2A/2C receptorselective antagonist in the same behavioral paradigm. These agents are chemically dissimilar and have different pharmacological profiles, but share with CP-293,019 its high affinity and selectivity for D 4 receptors Schlachter et al 1997;Millan et al 1998). …”

Section: Introductionmentioning

confidence: 99%

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Effects of dopamine D 4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

et al. 2002

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 55%

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Effects of dopamine D 4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

et al. 2002

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“…Using the EC 50 value of DA and the IC 50 value of each antagonist, respective K i estimates of 1.6, 1.5 and 66 nM were calculated, in good agreement with their expected potency at D4Rs. [33][34][35] It should be noted that in this and other studies, U-101958 displayed partial agonist activity (relative efficacy of 0.26 compared to dopamine) accounting for its partial inhibition of DAstimulated PLM. In contrast to these D4R antagonists, the presence of either the D2/D3-selective antagonist raclopride or the D1-receptor antagonist SCH23390 had no effect on DA-stimulated PLM at 1 M (Figure 4).…”

Section: D4 Receptor Involvement In Phospholipid Methylationsupporting

confidence: 57%

D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia

et al. 1999

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Keywords: receptors; G protein-coupled; phospholipid methylation; methionine; folic acid; membrane fluidity; purines; de novo synthesis Schizophrenia is a complex psychiatric disorder affecting approximately 1% of the population worldwide with a typical onset between the late teens and midthirties, often in the absence of significant prodromal psychiatric symptoms.1 Decades of research have yielded many theories on the origin of schizophrenia, although none provides a satisfying mechanistic explanation. Logically, dysfunctional neurotransmission is the most widely held theory, and specific abnormalities involving dopaminergic, 2 glutamatergic, 3 GABAergic 4 and nicotinic cholinergic 5 signaling have been proposed. Of these, the 'Dopamine Hypothesis' is dominant, based largely on the recognized therapeutic efficacy of drugs which block D2-like dopamine receptors (ie D2, D3 and D4 receptors), although their specific mechanism of benefit and the importance of individual receptor subtypes remains unclear. The D4

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“…Interestingly, apomorphine was a partial agonist, as were the compounds PD168077 and U-101958. PD168077 has been described as a selective, full agonist (Glase et al 1997), whereas U-101958 has been introduced as a selective antagonist at human dopamine D 4 receptors (Schlachter et al 1997). At the rat receptor, these two compounds appeared to display similar degrees of agonist intrinsic activity (efficacy 39% and 45%, respectively, relative to dopamine).…”

Section: Discussionmentioning

confidence: 99%

Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D 4 receptor

Gazi

Schoeffter

Nunn

et al. 2000

Naunyn-Schmiedeberg's Archives of Pharmacology

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It has been difficult to observe functional coupling of the D4 receptor to second messenger systems and a robust functional assay system for this receptor is still lacking. In the present study, the rat dopamine D4 receptor was cloned from rat retina. Sequence comparison revealed identity with the published sequence of Ashgari and co-workers, including the two amino acid insertions (V-Q) at position 92 which are not present in the published sequence of O'Malley and coworkers. The rat dopamine D4 receptor was stably expressed in Chinese hamster lung fibroblast CCL39 cells. [3H]spiperone saturation binding yielded a Bmax of 2,370+/-546 fmol/mg protein and a pKD of 8.74+/-0.14 (n=4). Forskolin-stimulated cAMP accumulation was inhibited by dopamine (Emax 61+/-1% inhibition of forskolin-stimulated levels, pEC50 7.33+/-0.06, n=23). A similar concentration-dependent inhibition was observed with the dopamine D2-like receptor agonists quinpirole and 7-OH-DPAT which elicited nearly the same Emax as dopamine. By contrast, apomorphine and a number of compounds with reported affinity for human dopamine D4 receptors (PD168077, U-101958, SDZ GLC 756, L-745,870 and NGD 94-1) behaved as partial agonists (Emax ranging between 26% and 56% of that of dopamine). The agonist effect of dopamine was completely blocked by preincubation with pertussis toxin, no further accumulation of cAMP above the forskolin-stimulated levels being observed. Antagonist pKB-values obtained against dopamine in this system were: 8.55+/-0.19 (n=3) for the partial agonist L-745,870, 8.38+/-0.23 (n=5) for spiperone, 7.18+/-0.17 (n=4) for haloperidol, 7.04+/-0.13 (n=4) for clozapine and <6 for raclopride. Other functional assays applicable were stimulation of [35S]GTPgammaS binding, extracellular acidification rate and a serum-responsive element using luciferase expression as a reporter gene. However, the receptor did not couple to phosphatidylinositol turnover or to intracellular Ca2+. Thus, expression of the rat dopamine D4 receptor in CCL39 cells provided several functional assay systems, of which inhibition of cAMP appeared to be the most robust one. These functional models can be used to evaluate the activity of compounds at the rat dopamine D4 receptor.

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Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor

Cited by 30 publications

References 13 publications

Effects of dopamine D 4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

Effects of dopamine D 4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia

Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D 4 receptor

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