Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y 5 receptor antagonists

Rueeger, Heinrich; Rigollier, Pascal; Yamaguchi, Yasuchika; Schmidlin, Tibur; Schilling, W; Criscione, Leoluca; Whitebread, Steven; Chiesi, Michele; Walker, Mary W.; Dhanoa, Dale; Islam, Imadul; Zhang, Jack; Gluchowski, Charles

doi:10.1016/s0960-894x(00)00177-3

Cited by 49 publications

(26 citation statements)

References 11 publications

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“…female rats at different phases of the estrus cycle. We A NPY-Y5 receptor antagonist, trans-naphtalene-1-sulaimed at studying the effects of leptin and the possible fonic acid-4-h(4-(3-dimethylamino-propylamino)-quinazolmediating role of NPY and CART in the regulation of in-2-ylamino)-methylj-cyclohexylmethylj-amide [25] GnRH secretion and the effects of leptin (10 M) were 2. Materials and methods studied using explants from 50-day-old female rats which were obtained in the morning or in the afternoon of each phase of the estrus cycle.…”

Section: Introductionmentioning

confidence: 99%

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Parent

Lebrethon

Gérard

et al. 2000

Regulatory Peptides

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Leptin may act as a negative feedback signal to the hypothalamic control of appetite through suppression of neuropeptide Y (NPY) secretion and stimulation of cocaine and amphetamine regulated transcript (CART). We aimed at studying the effects of leptin, CART and NPY on the hypothalamic control of the pituitary-gonadal system. Pulsatile gonadotropin-releasing hormone (GnRH) secretion was studied in vitro using retrochiasmatic hypothalamic explants from adult rats. In the female, GnRH pulse amplitude was significantly 27 26increased by leptin (10 M) and CART (10 M) irrespective of the estrus cycle phase while no such effects were seen in the male. The GnRH interpulse interval was not affected in both sexes. Passive immunoneutralization against CART caused a reduction in GnRH pulse 27 amplitude in the female. A slight but significant increase in GnRH pulse amplitude was caused by NPY (10 M) in the female. However, 26GnRH pulse amplitude was not affected by a Y5-receptor antagonist (10 M) while the interpulse interval was significantly increased as shown previously in the male. The increase in GnRH pulse amplitude caused by leptin was totally prevented by coincubation with an 27 anti-CART antiserum whereas it was not affected by coincubation with the NPY Y5-receptor antagonist (10 M). In conclusion, leptin and NPY show separate permissive effects on GnRH secretion in the adult rat hypothalamus. In both sexes, NPY is prominently involved in the control of the frequency of pulsatile GnRH secretion through the Y5 receptor subtype. Leptin causes a female-specific facilitatory effect on GnRH pulse amplitude which is mediated by CART and which occurs irrespective of the estrus cycle phase.

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Section: Introductionmentioning

confidence: 99%

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Parent

Lebrethon

Gérard

et al. 2000

Regulatory Peptides

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“…The 2,4-diaminoquinazoline motif was the scaffold of some early moderately active Y 5 antagonists with slight Y 1 /Y 5 selectivity [12]. Structural modifications led to the discovery of numerous quinazoline-type Y 5 antagonists with different substitution patterns [7,[12][13][14][15].…”

Section: Resultsmentioning

confidence: 99%

Preparation of Fluorescent Nonpeptidic Neuropeptide Y Receptor Ligands: Analogues of the Quinazoline‐type Anti‐obesity Y₅ Antagonist CGP 71683A

Mayer

Schneider

et al. 2003

Archiv der Pharmazie

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As part of a programme to develop fluorescence-based methods for the study of the interactions between G-protein coupled receptors (GPCRs) and their ligands the preparation of low molecular weight fluorescence-labelled neuropeptide Y (NPY) Y(5) antagonists is reported. The naphthylsulfonyl group in the potent quinazoline-type NPY Y(5) receptor antagonist CGP 71683A was replaced with a dansyl, nitrobenzoxadiazole (NBD) or acridine-9-carbonyl group. In radioligand binding studies on human Y(5) receptor expressing HEC-1B cells the substances labelled with acridine (K(i) 311 nM) and NBD (K(i) > 1000 nM) proved to be moderately active or inactive, respectively. By contrast, a K(i) value of 49 nM was found for the dansyl analogue compared to 2 nM for CGP 71683A. No binding to Y(1) receptors (SK-N-MC cells, displacement of [(3)H]propionyl-NPY) was detected for the new compounds at concentrations

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“…This was the case predominantly for its role in the occurrence of obesity in competition to NPY1. CGP 71683 (22) (Figure 5) was the first NPY5-R antagonist reported in the literature [127,128] with a K i of 1.4 and extremely high selectivity for NPY5-Rs.…”

Section: Non-peptide Ligands Of Npy Receptorsmentioning

confidence: 99%

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y 5 receptor antagonists

Cited by 49 publications

References 11 publications

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Preparation of Fluorescent Nonpeptidic Neuropeptide Y Receptor Ligands: Analogues of the Quinazoline‐type Anti‐obesity Y₅ Antagonist CGP 71683A

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y 5 receptor antagonists

Cited by 49 publications

References 11 publications

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y

Preparation of Fluorescent Nonpeptidic Neuropeptide Y Receptor Ligands: Analogues of the Quinazoline‐type Anti‐obesity Y5 Antagonist CGP 71683A

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

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Product

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Preparation of Fluorescent Nonpeptidic Neuropeptide Y Receptor Ligands: Analogues of the Quinazoline‐type Anti‐obesity Y₅ Antagonist CGP 71683A