Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents

Abstract

1 The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N- [[4-(aminocarbonylaminomethyl)phenyl]methyl]-N 2 -(diphenylacetyl)-argininamide tri¯uoroacetate) has been synthesized and was examined for its subtype selectivity, its in vitro antagonistic properties and its food intake inhibitory properties. 2 BIBO 3304 displayed subnanomolar anity for both the human and the rat Y1 receptor (IC 50 values 0.38+0.06 nM and 0.72+0.42 nM, respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low anity for both the human and rat Y1 receptor subtype (IC 50 41000 nM). BIBO 3304 showed low anity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC 50 values 41000 nM). 3 30 mg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 mg NPY as well as the hyperphagia induced by a 24 h fast implying a role for Y1 receptors in NPY mediated feeding. The inactive enantiomer had no eect. 4 BIBO 3304 inhibits neither the galanin nor the noradrenaline induced orexigenic response, but it blocked feeding behaviour elicited by both [Leu 31 , Pro 34 ]NPY and NPY (3 ± 36) suggesting an interplay between dierent NPY receptor subtypes in feeding behavior. 5 The present study reveals that BIBO 3304 is a subtype selective nonpeptide antagonist with subnanomolar anity for the Y1 receptor subtype that signi®cantly inhibits food intake induced by application of NPY or by fasting.

Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea‐pig

“…Since BIBO 3304 and H 409/22 do not block Y 5 receptors, their inhibitory actions on NPY induced food intake imply that Y 1 receptors are mediating this response. In agreement with the present results, it has been reported that BIBO 3304 inhibits NPY, (Leu 31 ,Pro 34 )NPY and NPY(2 ± 36) induced as well as fasting induced food intake in rats (Polidori et al, 2000;Wieland et al, 1998). The compound also inhibits the hyperphagia after orexin-A administration (Yamanaka et al, 2000), but not that NPY induced feeding in guinea-pigs A. Lecklin et alobtained after galanin or norepinephrine (Wieland et al, 1998).…”

“…Here, we have shown that NPY stimulates feeding behaviour also in guinea-pigs. Even if there are species di erences in the level of expression and distribution of the NPY receptor subtypes in the brain (Dumont et al, 1998;Gehlert & Gackenheimer, 1997), and in the binding characteristics of the cloned receptors Eriksson et al, 1998;StarbaÈ ck et al, 2000), NPY and its analogues, as well as the Y 1 and Y 5 antagonists, seemed to behave in a similar manner in guinea-pigs as reported earlier for rats (Haynes et al, 1998;Polidori et al, 2000;Wieland et al, 1998). Our results favour the hypothesis that both Y 1 and Y 5 receptors mediate NPY-induced food intake.…”

Neuropeptide Y Y1 receptor antagonism increases bone mass in mice

“…The Y1 receptor mediates remarkable effects in an extensive variety of important physiologic functions, namely in the regulation of feeding behaviour [20] and [21], energy balance [26] and adiposity [10] and [14], consistent with its wide distribution in central and peripheral tissues [24]. Therefore, an oral delivery of Y1 receptor antagonist might have been expected to induce some additional effects on other physiological systems besides bone.…”

“…The selective Y1 antagonist BIBO3304 was proven to significantly attenuate hyperphagia induced by intracerebroventricular NPY injection or following fasting [20] and [21]. In order to rule out potential side effects induced by the higher dose of BIBO3304, we evaluated the effects of 5 µmol BIBO3304 on spontaneous food intake after 1-and 5-weeks of treatment (termed 'acute' and 'chronic' treatment, respectively).…”

“…These agents represent powerful tools to determine the pharmacological potential of specifically targeting Y1 receptors for the benefit of disease treatment. Among these compounds, BIBO3304 remains one of the most potent and selective Y1 receptor antagonist described [20], with the added advantage that it can be administered orally. While, the therapeutic potential of antagonizing central Y1 receptors using centrally-administered BIBO3304 has been studied in vivo [20], [21] and [22], particularly with regard to feeding behaviour, this is the first study to explore the potential utility of orally-administered BIBO3304 as a therapeutic tool to improve bone mass.…”