The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226

Rudolf, K; Eberlein, Wolfgang; Engel, Wolfhard; Wieland, H.; Willim, Klaus-Dieter; Entzeroth, Michael; Weikel, W.; Beck‐Sickinger, Annette G.; Doods, Henri

doi:10.1016/0014-2999(94)90822-2

Cited by 348 publications

(201 citation statements)

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“…Pharmacologic evidence for the presence of Y1 and Y2 receptors consists of high-affinity and complete displacement of the universal ligand 125 I-hPYY by the Y1-selective analog [Leu 31 , Pro 34 ]-hPYY and the Y2-selective analog hPYY , respectively. These results are confirmed by comparable findings with the highly specific nonpeptide analogs BIBP 3226 for Y1 29 and BIIE 0246 for Y2. 30 The presence of Y4 or Y5 can be virtually ruled out based on the low affinity of the Y4-preferring hPP 6 and the inactivity of the Y5-selective analog [Ala 31 , Aib 32 ]-hNPY.…”

Section: Discussionsupporting

confidence: 78%

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Körner

Waser

Reubi

2005

Intl Journal of Cancer

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Numerous peptide receptors are overexpressed in human cancer, permitting in vivo tumor targeting. Among such receptors, those for the neurotransmitter neuropeptide Y (NPY) are overexpressed in various tumors. Since NPY can play a role in the kidney, NPY receptor expression and/or endogenous production of peptides of the NPY family (NPY, PYY, PP) were evaluated in 40 renal cell carcinomas (RCCs) and 18 nephroblastomas. NPY receptor protein expression was investigated by in vitro autoradiography using 125 I-labeled PYY in competition with NPY receptor subtype-selective analogs. NPY, PYY and PP production was assessed immunohistochemically. Fifty-six percent of RCCs expressed the Y1 receptor subtype in moderate density, and 80% of nephroblastomas expressed Y1 and Y2 subtypes in moderate to high density. Y1 was also highly expressed in intratumoral blood vessels. In selected cases, NPY was observed in nerve fibers in close association with intratumoral blood vessels and in the vicinity of tumor cells, while no PYY or PP was detected immunohistochemically in these sites. NPY receptors on renal tumor cells and tumor blood vessels may therefore be the molecular targets of endogenous NPY released by intratumoral nerve fibers. With regard to clinical applications, NPY receptors may act as in vivo targets for receptor-directed therapy of RCCs and nephroblastomas for which alternative therapeutic approaches are still required. ' 2005 Wiley-Liss, Inc.Key words: NPY receptor; renal cell carcinoma; nephroblastoma; receptor autoradiography Peptide hormone receptors are overexpressed in a wide variety of human tumors.1 Like other cell surface molecules, these receptors become increasingly important for clinical applications. In particular, they allow receptor-targeted tumor imaging and therapy with corresponding peptide hormone analogs. For instance, scintigraphy using the somatostatin analog Octreoscan is highly sensitive at detecting gastroenteropancreatic neuroendocrine tumors which express somatostatin receptors in high amounts.2,3 Moreover, targeted radiotherapy of these tumors with 90 Y-or 177 Lu-labeled somatostatin analogs is also promising. 4,5 Another peptide hormone receptor family with a potential future role in this field is the NPY receptor family. It belongs to the G protein-coupled receptor superfamily and comprises various subtypes. Subtypes Y1, Y2, Y4 and Y5 are expressed in humans. 6 They are present mainly in the central and peripheral nervous systems as well as other tissues, such as the cardiovascular system. Their physiologic ligands are the neurotransmitter NPY and the 2 hormones PYY and PP. Among many other sites, NPY has been localized to perivascular nerves in the human kidney. 7 NPY receptors may also play a role in human neoplasia. High incidence rates of subtypes Y1 and Y2 were found in tumors related to steroid hormone metabolism (adrenal cortical tumors, ovarian sex cord-stromal tumors, breast carcinomas), 8,9 in neuroendocrine tumors (pheochromocytomas and paragangliomas) 10

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Section: Discussionsupporting

confidence: 78%

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Körner

Waser

Reubi

2005

Intl Journal of Cancer

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“…In addition, the magnitude of this effect was similar to that observed with the highest dose of NPY (Figure 1, Panel A), suggesting that the involvement of other NPY receptor subtypes, other than Y 1 , is unlikely. However, as [Leu 31 Pro 34 ]PYY also has some agonist activity at Y 5 receptors (Michel et al 1998) (Rudolf et al 1994;Doods et al 1996)) and BIBO3304 (an antagonist showing ten times more potency for the Y 1 receptor than BIBP3226 (Wieland et al 1998)) completely blocked the antidepressant-like effects of NPY in the forced swim test. This matter will only be resolved with the advent of selective NPY Y 5 receptor antagonists, which are not yet widely available.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned earlier, it could be postulated that the effects seen in the mouse forced swim following [Leu 31 Pro 34 ]PYY (an NPY Y 1 receptor agonist (Dumont et al 1998;Michel et al 1998)) administration may have been mediated by both NPY Y 1 and Y 5 receptors. However, this seems unlikely as BIBP3226 (an NPY Y 1 receptor antagonist with very low affinity for NPY Y 5 receptors (Rudolf et al 1994;Doods et al 1996)) and BIBO3304 (an antagonist showing ten times more potency for the Y 1 receptor than BIBP3226 (Wieland et al …”

mentioning

confidence: 99%

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

Redrobe

Dumont

Fournier

et al. 2002

Neuropsychopharmacology

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The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY)inNeuropeptide Y (NPY) is a 36-amino acid peptide that is widely distributed in the central nervous system (CNS). Intracerebroventricular (ICV) administration of NPY stimulates food intake (Clark et al. 1985;Levine and Morley 1984;Stanley and Leibowitz 1984), modulates cognition (Flood et al. 1987;Redrobe et al. 1999), inhibits neuronal excitability (Colmers and Bleakman 1994) and has anticonvulsant effects (Vezzani et al. 1999). NPY modulates the secretion of various hypothalamic neuropeptides, stimulates the corticotrophic axis (Krysiak et al. 1999;Small et al. 1997) and has potent inhibitory effects on gonadotrophic and somatotrophic axes (Catzeflis et al. 1993). In addition, NPY is thought to play a role in the pathophysiology of certain mood disorders and in the mechanism of action of antidepressant drugs (Heilig et al. 1988;Caberlotto et al. 1998 (Michel et al. 1998).Clinical studies have demonstrated decreased NPY levels in the cerebrospinal fluid (CSF) (Heilig and Widerlov 1990) and plasma (Nilsson et al. 1996) of depressed patients, when compared with healthy control subjects. In addition, NPY levels have been shown to be negatively correlated to scores of anxiety in clinically depressed patients (Heilig and Widerlov 1990), suggesting a possible link between low levels of NPY and predisposition to anxiety-related or stress-induced depression.Moreover, pre-clinical studies have shown that electroconvulsive shock stimulation increased NPY gene expression (Heilig et al. 1988), as well as the expression of NPY mRNA in distinct brain regions in rats (Caberlotto et al. 1998;Mikkelsen et al. 1994). In addition, chronic antidepressant treatment has been shown to alter NPY and NPY Y 1 -type receptor mRNA levels (Caberlotto et al. 1998), and to reduce NPY Y 2 -type receptor densities in certain brain regions (Widdowson and Halaris 1991). Interestingly, NPY-like immunoreactivity and NPY Y 1 -type receptor binding sites were shown to be decreased or increased, depending on the brain region studied, in the recently developed Flinders Sensitive Line (FSL) rats (Caberlotto et al. 1999), a purported genetic animal model of depression (Overstreet 1993;Overstreet et al. 1995).Additional evidence of a role for NPY in depressive disorders is found in studies using the olfactory bulbectomized (OB) rat model of depression. Sub-chronic ICV administration of NPY attenuated the increase in ambulation, rearing, grooming and defecation scores consistently found when OB animals are tested in the open field (Song et al. 1996). Treatment with NPY also increased noradrenaline (NA) and serotonin (5-HT) levels in the amygdala and hypothalamus (Song et al. 1996). In addition, NPY reversed the supression of lymphocyte proliferation seen following OB (Song et al. 1994). A decrease in lymphocyte proliferation has also been reported in depressed patients (Kronfol and House 1989). Another study demonstrated that OB caused long term...

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“…Of these, BIBP3226 was the first highly-potent, high affinity NPY Y 1 antagonist that had low affinity for other NPY Y receptor subtypes. 162,163 After administration into the brain, this compound either partially or completely reversed the increase in food intake produced by NPY, [Leu 31 , Pro 34 ] NPY and hPYY . BIBP3226 and also decreased the refeeding response to short-term fasting and the intake of highly palatable food.…”

Section: Npy Receptor Subtypesmentioning

confidence: 97%

Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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AIM:The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y 1 receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y 2 and NPY Y 5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.

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The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP3226

Cited by 348 publications

References 6 publications

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

Appetite suppression based on selective inhibition of NPY receptors

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