Benextramine-neuropeptide Y (NPY) binding site interactions: Characterization of 3H-NPY binding site heterogeneity in rat brain

Doughty, Michael B.; Li, K.; Chu, Shao Song; Tessel, Richard E.

doi:10.1016/0143-4179(92)90119-h

Cited by 17 publications

(8 citation statements)

References 24 publications

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“…It was demonstrated that BXT incubated for 30 min at 10 gM followed by 30 min of washing, completely inhibited the smooth muscle contractile response to NA of the whole isolated vas deferens of the rat (Melchiorre et al, 1978). However, it was recently claimed that BXT at high concentrations (200 and 1000 gM) is also able to block selectively Y1 but not Y2 receptors in ligand binding studies performed with rat brain membranes (Doughty et al, 1992). Using the rat isolated femoral artery the same group reported that BXT, incubated for 10 mmi at 10 jiM, antagonized, probably in an irreversible manner, [Leu31,Pro-4]NPY and NPY 336-induced contractions.…”

Section: Discussionmentioning

confidence: 99%

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens

Palea¹,

Corsi²,

Rimland³

et al. 1995

British J Pharmacology

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3 The putative NPY antagonist, PYX-2, incubated at 1 ,UM for 20 min, was completely ineffective in antagonizing PYY-induced inhibition of twitches.4 The twitch response was totally inhibited by suramin (100 gM) but was little affected by prazosin (1 gM). Futhermore, NPY was without effect on the dose-response curve to ATP in resting conditions. Taken together, these results suggest that in our paradigm, NPY inhibits the release of a purinergic neurotransmitter which mediates contraction of the prostatic portion of the rat vas deferens.

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Section: Discussionmentioning

confidence: 99%

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens

Palea¹,

Corsi²,

Rimland³

et al. 1995

British J Pharmacology

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“…been caused by residual NPY binding repeatedly to NPY receptors after bath washout, the putative NPY receptor antagonist benextramine was used. This antagonist has been reported to block Yl and Y2 receptors, but it may not be fully effective at all NPY receptors (Li et al, 1991;Doughty et al, 1992;Penner et al, 1993;Palea et al, 1995). If residual NPY was binding repeatedly to NPY receptors, and thereby causing long-term calcium depression, the displacement of NPY with benextramine should cause a rapid Ca*+ elevation.…”

Section: Npy-mediatedmentioning

confidence: 99%

Neuropeptide Y Depresses GABA-Mediated Calcium Transients in Developing Suprachiasmatic Nucleus Neurons: A Novel Form of Calcium Long-Term Depression

Obrietan

Pol

1996

J. Neurosci.

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In contrast to its inhibitory role in mature neurons, GABA can exert excitatory actions in developing neurons, including mediation of increases in cytosolic Ca2+. Modulation of this excitatory activity has not been studied previously. We used Ca2+ digital imaging with Fura-2 to test the hypothesis that neuropeptide Y (NPY) would depress GABA-mediated Ca2+ rises in neurons cultured from the developing suprachiasmatic nucleus (SCN). SCN neurons were chosen as a model system for this study because SCN neurons are primarily GABAergic, they express high levels of NPY and GABA receptors, and functionally, NPY causes profound phase-shifts in SCN-generated circadian rhythms. Vigorous GABA-mediated Ca2+ activity was found in young SCN neurons that were maintained in vitro for 4-14 d. NPY showed a dose-dependent rapid depression of the amplitude of Ca2+ rises generated by GABA released from presynaptic SCN axons. NPY exerted a long-term depression of cytosolic CA2+ in the majority of neurons tested, which lasted more than 1 hr after NPY washout. The magnitude of the NPY depression was dose-dependent. NPY did not affect Ca2+ levels when GABAA receptor activity was blocked by bicuculline; however, when bicuculline and NPY were withdrawn from the perfusion solution, the subsequent CA2+ rise was either significantly reduced or completely absent, suggesting that the NPY receptor was activated in the absence of elevated intracellular Ca2+ and GABAA receptor activity, and that the latent effect of NPY was revealed only after depolarizing GABA stimulation was renewed. Pretreating neurons with pertussis toxin greatly reduced the ability of NPY to depress GABAergic Ca2+ rises, suggesting that the NPY modulation of the GABA activity was based largely on a mechanism involving pertussis toxin-sensitive Gi/Go proteins. NPY receptor stimulation depressed (< 30%) postsynaptic Ca2+ rises evoked by GABA (20 microM) application in the presence of tetrodotoxin (TTX). The effects of NPY were mimicked by the NPY Y1 receptor agonist [Pro34,Leu31] NPY and the Y2 receptor agonist NPY 13-36 and by peptide YY (PYY). Together, our data suggest that the Y1 and Y2 type NPY receptors act both presynaptically and postsynaptically to depress GABA-mediated Ca2+ rises. If related mechanisms exist in peptide modulation of inhibitory GABA activity in mature neurons, this could underlie long-term changes in the behavior of neurons of the SCN necessary for phase-shifting the circadian clock by NPY, NPY also modulated GABA responses in neuroendocrine neurons from the hypothalamic arcuate nucleus. NPY thus can play an important role in evoking long-term depression of GABA-mediated Ca2+ activity in these developing neurons, allowing NPY-secreting cells to modulate the effects of GABA on neurite outgrowth, gene expression, and physiological stimulation. This is the first example of such a cellular memory: that is, long-term Ca2+ depression based on modulation of depolarizing GABA activity.

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“…ic Acid IV-Hydroxysuccinimide Ester (8a). A solution of dicyclohexylcarbodiimide (2.7 g, 13.2 mmol) in CH2C12 (50 mL) was added dropwise to a stirred solution of 7a (4.9 g, 12.0 mmol) and N-hydroxysuccinimide (1.6 g, 13.9 mmol) in CH2C12 (350 mL) at 0 °C. The solution was allowed to stir for 4 h and then kept in the refrigerator for 10 h. The precipitated solid was removed by filtration, and the filtrate was evaporated at reduced pressure to afford a viscous residue.…”

Section: -[Jv-carbobenzoxy-jv-(2-naphthylmethyl)aniino]hexano-mentioning

confidence: 99%

“…6 Our laboratories reported the first nonpeptide antagonist of the neuropeptide Y receptor with both in vitro and in vivo activity.9 Benextramine (2), a tetraamine disulfide first designed by Melchiorre as an irreversible adrenergic receptor antagonist,10 is also equipotent as a NPY receptor Asp-Ala-Pro-Ala-Glu-Asp-Leu-Ala-Arg-Tyr- Tyr-Ser-Ala-Leu-Arg-His-Tyr-lle-Asn-Leu- sensitive binding sites in rat brain are of the subtype while the benextramine-insensitive sites are of the Y2 subtype. 13 This evidence first demonstrated a distinct difference between the rat brain Y2 receptor and the postsynaptic Y2 receptor in the rat periphery. In addition, Michel and Motulsky14 reported that He90481 is a nonpeptide antagonist of NPY receptors in vitro.…”

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confidence: 95%

Nonpeptide Peptidomimetic Antagonists of the Neuropeptide Y Receptor: Benextramine Analogs with Selectivity for the Peripheral Y2 Receptor

Chaurasia

Misse²,

Tessel³

et al. 1994

J. Med. Chem.

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We synthesized a new series of benextramine analogs as neuropeptide Y (NPY) functional group mimetics and tested them for N-[propionyl-3H]NPY ([3]NPY) displacement activity in rat brain membrane homogenates and for NPY receptor antagonist activity in the rat femoral artery. The tetraamine, carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-1,6-hexanediamine (15) was equipotent with benextramine (based on comparison of the relevant IC50's) in a rat brain [3H]NPY displacement assay, suggesting that the disulfide is not a necessary feature of benextramine's [3H]NPY displacement activity, although this analog maintained selectivity for the benextramine-sensitive binding site population. The bis(N,N-dialkylguanyl) disulfide and carbon analogs 14a-c were 3-4 times more potent than their respective controls in displacing [3H]NPY from rat brain membrane homogenates with IC50's ranging from 15 to 18 microM and maintained selectivity for the benextramine-sensitive, Y1 binding site population. However, the activity of the carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-N,N'-(1,6- hexanediyl)diguanidine tetrahydrochloride (14b) showed a different profile in a femoral artery vasoconstriction assay; at 1.0 nM, this analog shifted the concentration-effect curve of the Y2-selective agonist NPY13-36 to the right (pA2 = 9.2; Kd = 0.63 nM) without a significant change in the maximum effect, while even at 1.0 mM it had no effect on the vasoconstrictive activity of the Y1-selective agonist [Leu31,Pro34]NPY. Thus, the bis(N,N-dialkylguanidine) analogs of benextramine are selective, competitive antagonists of the postsynaptic NPY receptor in the femoral artery.

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Benextramine-neuropeptide Y (NPY) binding site interactions: Characterization of 3H-NPY binding site heterogeneity in rat brain

Cited by 17 publications

References 24 publications

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens

Neuropeptide Y Depresses GABA-Mediated Calcium Transients in Developing Suprachiasmatic Nucleus Neurons: A Novel Form of Calcium Long-Term Depression

Nonpeptide Peptidomimetic Antagonists of the Neuropeptide Y Receptor: Benextramine Analogs with Selectivity for the Peripheral Y2 Receptor

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Benextramine-neuropeptide Y (NPY) binding site interactions: Characterization of 3H-NPY binding site heterogeneity in rat brain

Cited by 17 publications

References 24 publications

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y2 receptors in rat isolated prostatic vas deferens

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y2 receptors in rat isolated prostatic vas deferens

Neuropeptide Y Depresses GABA-Mediated Calcium Transients in Developing Suprachiasmatic Nucleus Neurons: A Novel Form of Calcium Long-Term Depression

Nonpeptide Peptidomimetic Antagonists of the Neuropeptide Y Receptor: Benextramine Analogs with Selectivity for the Peripheral Y2 Receptor

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Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens

Failure of the putative neuropeptide Y antagonists, benextramine and PYX‐2, to inhibit Y₂ receptors in rat isolated prostatic vas deferens