Delving into the Latest Updates on Lu AA-33810 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LU AA 33810

Target

NPY5R

Mechanism

NPY5R antagonists(Neuropeptide Y receptor type 5 antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication

Nervous System Diseases

Inactive Indication-

Originator Organization

H. Lundbeck A/S

Active Organization

H. Lundbeck A/S

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC19H25N3O2S3

InChIKeyUWSBTSAJZMIHBL-HDJSIYSDSA-N

CAS Registry304008-29-5

It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model.

OBJECTIVE:

In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression.

RESULTS:

We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810.

CONCLUSION:

Our results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.

01 Dec 2011·PsychopharmacologyQ3 · MEDICINE

A role for neuropeptide Y Y5 but not the Y1-receptor subtype in food deprivation-induced reinstatement of heroin seeking in the rat

Q3 · MEDICINE

Article

Author: Uri Shalev ; Firas Sedki ; Nick Schoela ; Tia Maric ; Danielle Chafetz

RATIONAL AND OBJECTIVES:

Neuropeptide Y (NPY), an orexigenic peptide that is released during periods of food restriction, has been shown to have a significant modulatory impact on drug-related behaviors. We have previously reported that both acute food deprivation (FD) and NPY injections can reinstate extinguished drug-seeking behavior, a proposed animal model of relapse to drug abuse. However, it is not clear whether the FD effect on drug seeking is dependent on NPY transmission. Here, we used the reinstatement model to assess the role of NPY Y1 and Y5-receptor-mediated transmission in FD-induced reinstatement of heroin seeking.

METHODS:

Rats were trained to self-administer heroin for 10-12 days (0.1 mg/kg/infusion/intravenous). Animals then underwent extinction training followed by drug-seeking reinstatement tests under 21 h of FD and sated conditions.

RESULTS:

Injections of a novel NPY Y5-receptor antagonist, Lu AA33810 (0.0, 1.0, or 30.0 mg/kg/IP), resulted in a significant attenuation of FD-induced reinstatement of extinguished heroin seeking. However, no significant effects on reinstatement were found for the Y1-receptor antagonist, BIBO 3304 (0.0, 5.0, or 10.0 nmol/intracerebroventricular).

CONCLUSIONS:

These results suggest that while signals mediated through NPY Y1 receptors play a modest role in reinstatement, activation of Y5 receptors has a critical function in FD-induced reinstatement of heroin-seeking behavior.

01 Sep 2011·Bioorganic & medicinal chemistry lettersQ4 · MEDICINE

Discovery of Lu AA33810: A highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder

Q4 · MEDICINE

Article

Author: Ove. Wiborg ; Wai C. Wong ; Toni D. Wolinsky ; Hualing Zhong ; Mary W. Walker ; Gamini Chandrasena ; Stewart A. Noble ; Mahesh Desai ; Kim Andersen ; Yalei Lu ; Vrej Jubian ; Mathivanan Packiarajan ; Mohammad R. Marzabadi

The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.

100 Deals associated with Lu AA-33810

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