Rationally Based Efficacy Tuning of Selective Dopamine D4 Receptor Ligands Leading to the Complete Antagonist 2-[4-(4-Chlorophenyl)piperazin-1- ylmethyl]pyrazolo[1,5-<i>a</i>]pyridine (FAUC 213)

Löber, Stefan; Hübner, Harald; Utz, Wolfgang; Gmeiner, Peter

doi:10.1021/jm015522j

Cited by 95 publications

(77 citation statements)

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“…For example, FAUC213, CP293,019, and Ro61-6270 are antagonists (Hartmann et al, 1996;Sanner et al, 1998;Lober et al, 2001); FAUC113, NGD 94-1, L750,667, and RBI257 are weak partial agonists (Gazi et al, 1998(Gazi et al, , 1999Lober et al, 2001); and PD168,077 and CP226,269 are agonists (Glase et al, 1997;Zorn et al, 1997), yet each of these ligands display mode-1 binding. Likewise, within mode-3 binding compounds there is no apparent correlation with their functional properties, because whereas PNU101,387G is an antagonist (Merchant et al, 1996), Ro10-4548 is an agonist (C. Riemer, personal communication).…”

Section: Discussionmentioning

confidence: 99%

“…FAUC113 and FAUC213 were synthesized as described previously (Lober et al, 2001). All other drugs were either purchased from Sigma/RBI (Natick, MA) or received as generous gifts from the various sources listed under Acknowledgments.…”

Section: Methodsmentioning

confidence: 99%

“…It has been demonstrated that L745,870-like derivatives such as FAUC113 also have weak partial agonist activity, which can be completely eliminated by a 2Ј substitution, rather than a 3Ј substitution, of the diazole moiety of the heterocyclic ring (Lober et al, 2001). The assignment of the 2Ј-substituted diazole FAUC213 as a "neutral antagonist" using different measures of functional activity (fluorometric imaging plate reader G␣ qo5 -based versus mitogenesis-based) has been discussed recently (Stewart et al, 2004).…”

Section: Abbreviationsmentioning

confidence: 99%

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Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

et al. 2004

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We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo [2,3-b]pyridine] and the D2-selective ligands methylspiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl) et al., 2000). Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and molecular models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20 -96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2-selective methylspiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.Dopamine receptors belong to the class A family of G protein-coupled receptors (GPCRs) that share a rhodopsin-like structure. In humans and mammals, the dopamine receptor family is comprised of five genotypically distinct members, which are subclassified as D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors on the basis of their similarities in structure, G protein-coupling preferences, and pharmacology. After the discovery that antipsychotic efficacy strongly correlates with the strength of D2 receptor antagonism (Creese et al., 1976), it was realized that not one, but three subtypes of D2-like receptors existed and that many antipsy-

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Abbreviationsmentioning

confidence: 99%

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Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

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“…As the clinical potencies of typical neuroleptics, like haloperidol, seem to be intimately correlated with their D 2 receptor affinities (reviewed by Snyder 1996), the fact that some of these drugs also exhibit remarkable binding properties towards the other D 2 -like receptors also aroused fundamental interest in the D 3 and D 4 receptor subtype. Moreover, the considerable pharmacological profile of the atypical antipsychotic clozapine has focused special attention on the D 4 receptor, since it shows a moderate 2-fold to 5-fold preference for D 4 over D 2 (Chabert et al 1994;Roth et al 1995;Newman-Tancredi et al 1997;Löber et al 2001) and good correlations between the clinically efficacious dose and its D 4 affinity (Seeman 1995;. It also shows superior efficacy in refractory schizophrenia and negative symptoms such as amotivation and social withdrawal, as well as a minimal risk or even absence of side effects such as the extrapyramidal symptoms (EPS) and elevation of the prolactin level (reviewed by Remington and Kapur 2000).…”

Section: Introductionmentioning

confidence: 99%

“…For instance U-101958, a prominent D 4 selective antagonist, was found to exhibit some agonistic activity (Gazi et al 1998(Gazi et al , 1999. In contrast, 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) was shown to be not only highly D 4 selective (Table 1), but also a complete antagonist with less than 3% agonistic activity compared with the full agonist quinpirole (Löber et al 2001). FAUC 213 was therefore considered worthy of having its biological profile examined with methods of behavioural neurobiology and neurochemistry as described in this article.…”

Section: Introductionmentioning

confidence: 99%

FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

Boeckler¹,

Russig²,

Zhang³

et al. 2004

Psychopharmacology

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Rationale: 2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo [1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D 4 receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay. Objectives: In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry. Methods: Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study. Results: A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/ kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex.The selective D 4 antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D 2 receptor antagonism, but a partial involvement of 5-HT 2 -and α 1 -receptors cannot be ruled out at present. Conclusions: We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.

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Bicyclic Pyridines Containing Ring‐Junction Nitrogen

2018

Privileged Structures in Drug Discovery

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Rationally Based Efficacy Tuning of Selective Dopamine D4 Receptor Ligands Leading to the Complete Antagonist 2-[4-(4-Chlorophenyl)piperazin-1- ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213)

Cited by 95 publications

References 28 publications

Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia

Bicyclic Pyridines Containing Ring‐Junction Nitrogen

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