In vitro pharmacological profile of YM‐43611, a novel D2‐like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors

Hidaka, Kazuyuki; Tada, Shoko; Matsumoto, Mitsuyuki; Ohmori, Junya; Tasaki, Yoshikazu; Nomura, Tamako; Usuda, Shinji; Yamaguchi, Tokio

doi:10.1111/j.1476-5381.1996.tb15332.x

Cited by 17 publications

(20 citation statements)

References 33 publications

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“…The generation of plasma cells requires naïve B (nB) cell activation via germinal center (GC) reactions 3 to undergo affinity maturation by somatic hypermutation as they differentiate into in high affinity ASC or memory B cells 4 . Alternatively, nB cells can also undergo extrafollicular (EF) reactions outside the GC and directly differentiate into ASC as described initially in mice models of Ehrlichia muris, Salmonella enterica serovar Typhimurium, and Borrelia burgdorferi [5][6][7][8][9][10][11][12][13][14][15] and more recently in humans in autoimmunity and primary viral infections such as SARS-CoV-2 [16][17][18][19] . Reports have shown that a primary immune response can initiate class switching prior to GC formation [20][21][22] , and more recently, that class switching predominantly takes place at the T-B border and infrequently in the GC 23 .…”

Section: Introductionmentioning

confidence: 99%

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

et al. 2021

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Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.

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Section: Introductionmentioning

confidence: 99%

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

et al. 2021

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“…Expression and Functional Assay-Rabbit Y2b, human Y2b, and the reverted-mutant cDNA were ligated into mammalian expression vector pEF-BOS(dhfr) containing dhfr gene as a selective marker (14,15). For transient expression study, the plasmid constructs and no inserted vector were separately transfected into COS-1 cells as described previously (13).…”

Section: Methodsmentioning

confidence: 99%

“…For transient expression study, the plasmid constructs and no inserted vector were separately transfected into COS-1 cells as described previously (13). To establish a rabbit Y2b expressed cell line, the plasmid construct was transfected into CHO(dhfr Ϫ ) cells using LipofectAMINE (Life Technologies, Inc.) as described previously (15). The transfected cells were divided into single cells, and a monoclonal cell line showing specific 125 I-porcine PYY binding was used for pharmacological characterization.…”

Section: Methodsmentioning

confidence: 99%

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Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species

Matsumoto¹,

Nomura²,

Momose³

et al. 1996

Journal of Biological Chemistry

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136

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Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related peptides which have numerous functions in both neural and endocrine signaling. By homology screening, we cloned a novel gene sharing the highest homology with the NPY Y1 receptor gene from humans, rabbits, and several other species. This novel gene of rabbit encodes a functional NPY/PYY receptor, designated Y2b, which prefers NPY 13-36 rather than [Leu 31 ,Pro 34 ]NPY despite its higher identity with the Y1 receptor. Although, at low levels, mRNA was detected in the tissues and brain regions, including hypothalamus. Further, sequence data revealed that this gene is the orthologue of the recently cloned mouse novel NPY receptor, Y5. However, our study demonstrates that the receptor function of this gene has been inactivated in primates by a frameshift mutation occurring early in primate evolution. This novel NPY receptor represents the first neurotransmitter receptor identified that has universally lost its receptor function in primate species. Interestingly, despite its inactivation in humans, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene.Neuropeptide Y (NPY), 1 peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related 36-amino acid peptides which have functions in both neural and endocrine signaling. These peptides exert their actions via receptors on the targeted neurons and peripheral cells. Several receptor subtypes have been defined by their ability to bind NPY, PYY, PP, and derivatives of these peptides. Earlier studies classified this receptor family into at least three receptor subtypes, Y1, Y2, and Y3 (1). The existence of additional receptors were also proposed, "atypical" Y1 receptor (mediating the feeding response of NPY in hypothalamus), PP-preferring receptor (exerting PP activity), and PYY-preferring receptor (2, 3). Molecular cloning studies have revealed the structure of Y1, Y2, and Y4/PP1 receptors (4 -9). These are all heptahelix (seven-transmembrane regions) receptors which couple to G-proteins. The Y4/PP1 receptor has higher affinity for PP than PYY and NPY, suggesting this receptor to be a member of PP receptors.As yet unknown members of this NPY receptor family are expected to be identified by molecular cloning. Very recently, during the course of the present work, the cloning and characterization of mouse Y5 (10) and rat Y5 (11) receptors was reported. The mouse Y5 receptor has significant homology with the Y1 receptor, but the rat Y5 receptor has little identity with the previously cloned NPY receptors, showing that these receptors are not species orthologues, despite having the same name, Y5. In the present report, we describe the cloning of a novel gene sharing the highest homology with the Y1 receptor from humans, rabbits, and several other species. Our study revealed that this novel gene is the orthologue of the mouse Y5 receptor gene (10) and encodes functional ...

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“…A number of dopamine D 4 ligands, including 5‐(4‐chlorophenyl)‐4‐methyl‐3‐(1‐(2‐phenylethyl)piperidin‐4‐yl) isoxazole (Rowley et al , 1996), 3‐[[4‐(4‐chlorophenyl)piperazin‐1‐yl]‐methyl]‐1H‐pyrrolol[2,3‐b]pyridine (Kulagowski, et al , 1996), (S)‐(–)‐4‐[4‐[2‐(isochroman‐1‐yl) ethyl]‐piperazin‐1‐yl] benzonesulphonamide (TenBrink et al , 1996), JL18 (Leigeois et al , 1995), 2‐naphthoate esters (Boyfield et al , 1996) and YM‐43611 (Hidaka et al , 1996; Ohmori et al , 1996) have been developed. However, in vivo dopamine D 4 receptor antagonism, potency and antipsychotic activity of these compounds have not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

The atypical antipsychotic profile of NRA0045, a novel dopamine D₄ and 5‐hydroxytryptamine_2A receptor antagonist, in rats

Okuyama

Chaki

Kawashima

et al. 1997

British J Pharmacology

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1 The atypical antipsychotic pro®le of (R)-(+)-2-amino-4-(4-¯uorophenyl)-5-[1-[4-(4-¯uorophenyl)-4-oxobutyl] pyrrolidin-3-yl] thiazole (NRA0045), a potent dopamine D 4 and 5-hydroxytryptamine (5-HT) 2A receptor antagonist, was examined in rats. 2 Spontaneous locomotor activity was decreased dose-dependently with i.p. administration of clozapine (ED 50 3.7 mg kg 71 ), haloperidol (ED 50 0.1 mg kg 71 ) and chlorpromazine (ED 50 0.9 mg kg 71 ), whereas inhibition of this type of behaviour induced by i.p. administration of NRA0045, at doses up to 10 mg kg 71 , did not exceed 50%. 3 Locomotor hyperactivity induced by methamphetamine (MAP, 2 mg kg 71 , i.p.) in rats (a model of antipsychotic activity) was dose-dependently antagonized by NRA0045 (ED 50 0.4 mg kg 71 , i.p., and 0.3 mg kg 71 , p.o., respectively), clozapine (ED 50 0.3 mg kg 71 , i.p. and 0.8 mg kg 71 , p.o., respectively), haloperidol (ED 50 0.02 mg kg 71 , i.p. and 0.1 mg kg 71 , p.o., respectively), chlorpromazine (ED 50 0.3 mg kg 71 , i.p. and 3.3 mg kg 71 , p.o., respectively). In contrast, the MAP (3 mg kg 71 , i.v.)-induced stereotyped behaviour in rats (a model of extrapyramidal symptoms) was not a ected by NRA0045 or clozapine, at the highest dose given (30 mg kg 71 , i.p.). Haloperidol (ED 50 0.3 mg kg 71 , i.p.) and chlorpromazine (ED 50 4.8 mg kg 71 , i.p.) strongly blocked the MAP-induced stereotyped behaviour. NRA0045 and clozapine selectively blocked behaviour associated with activation of the mesolimbic/ mesocortical dopamine neurones rather than nigrostriatal dopamine neurones. 4 Extracellular single-unit recording studies demonstrated that MAP (1 mg kg 71 , i.v.) decreased the ®ring rate in the substantia nigra (A9) and ventral tegmental area (A10) dopamine neurones in anaesthetized rats. NRA0045 completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 0.1 mg kg 71 , i.v.), whereas the inhibitory e ects of MAP on A9 dopamine neurones were not a ected by NRA0045, in doses up to 1 mg kg 71 (i.v.). Clozapine completely reversed the inhibitory e ects of MAP on A10 dopamine neurones (ED 50 1.9 mg kg 71 , i.v.) and on A9 dopamine neurones (ED 50 2.5 mg kg 71 , i.v.). Haloperidol completely reversed the inhibitory e ects of MAP on A10 (ED 50 0.03 mg kg 71 , i.v.) and on A9 dopamine neurones (0.02 mg kg 71 , i.v.). NRA0045, like clozapine, was more potent in reversing the e ects of MAP on A10 than A9 dopamine neurones. 5 Prepulse inhibition (PPI) is impaired markedly in humans with schizophrenia. The disruption of PPI in rats by apomorphine (0.5 mg kg 71 , s.c.) was reversed signi®cantly by NRA0045 (3 mg kg 71 , i.p.), clozapine (3 mg kg 71 , i.p.) and haloperidol (0.3 mg kg 71 , i.p.). 6 Phencyclidine (PCP) elicits predominantly psychotic symptoms in normal humans and in schizophrenics. NRA0045 (0.03 ± 0.3 mg kg 71 , i.p.) and clozapine (0.1 ± 1 mg kg 71 , i.p.) signi®cantly and dose-dependently shortened the PCP(1.25 mg kg 71 , i.p.)-induced prolonged swimming latency in rats in a water maze task, whereas haloperidol (...

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In vitro pharmacological profile of YM‐43611, a novel D₂‐like receptor antagonist with high affinity and selectivity for dopamine D₃ and D₄ receptors

Cited by 17 publications

References 33 publications

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species

The atypical antipsychotic profile of NRA0045, a novel dopamine D₄ and 5‐hydroxytryptamine_2A receptor antagonist, in rats

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In vitro pharmacological profile of YM‐43611, a novel D2‐like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors

Cited by 17 publications

References 33 publications

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Extrafollicular IgD+ B cells generate IgE antibody secreting cells in the nasal mucosa

Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species

The atypical antipsychotic profile of NRA0045, a novel dopamine D4 and 5‐hydroxytryptamine2A receptor antagonist, in rats

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Resources

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In vitro pharmacological profile of YM‐43611, a novel D₂‐like receptor antagonist with high affinity and selectivity for dopamine D₃ and D₄ receptors

The atypical antipsychotic profile of NRA0045, a novel dopamine D₄ and 5‐hydroxytryptamine_2A receptor antagonist, in rats