Delving into the Latest Updates on AVL-3288 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Compound 6 (N-(4-chlorophenyl)-α-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide)

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Target

CHRNA7

Mechanism

CHRNA7 positive allosteric modulator(Neuronal acetylcholine receptor protein alpha-7 subunit positive allosteric modulator)

Therapeutic Areas

Other DiseasesNervous System Diseases

Active Indication

Central Nervous System DiseasesCognitive Dysfunction

Inactive Indication

Schizoaffective disorderSchizophrenia

Originator Organization

Anvyl Pharmaceuticals

Active Organization

University of California, Irvine

Inactive Organization

National Institute of Mental Health

University of Maryland BaltimoreAnvyl LLC

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Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H15Cl2N3O2

InChIKeyVMAKIACTLSBBIY-UHFFFAOYSA-N

CAS Registry917837-54-8

Single-center, randomized, double-blind, placebo-controlled, proof-of-principle study to evaluate potential cognitive benefits of a single oral dose of AVL-3288 (3 mg) in the presence and absence of transdermal nicotine (7 mg/24 hrs) in healthy non-smokers, while monitoring the safety and tolerability of AVL-3288.

Start Date01 May 2018

Sponsor / Collaborator

University of Maryland Baltimore

NCT02978599 / CompletedPhase 1IIT

Double Blind, Two Dose, Cross-over Clinical Trial of the Positive Allosteric Modulator at the alpha7 Nicotinic Cholinergic Receptor AVL-3288 in Schizophrenia Patients

Single-center, outpatient, randomized, double-blind, placebo-controlled, 3-treatment-phase, cross-over study to evaluate the safety, tolerability and efficacy of two oral doses of AVL-3288 each compared to placebo, in patients with schizophrenia.

Start Date01 Nov 2016

Sponsor / Collaborator

The New York State Psychiatric Institute

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100 Clinical Results associated with AVL-3288

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100 Translational Medicine associated with AVL-3288

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100 Patents (Medical) associated with AVL-3288

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10

Literatures (Medical) associated with AVL-3288

01 Aug 2024·Pharmacology Biochemistry and Behavior

Chronic administration of caffeine, modafinil, AVL-3288 and CX516 induces time-dependent complex effects on cognition and mood in an animal model of sleep deprivation

Article

Author: Paykal, Gökçen ; Aykan, Utku ; Güvel, Muhammed Cihan ; Uluoğlu, Canan

OBJECTIVECaffeine and modafinil are used to reverse effects of sleep deprivation. Nicotinic alpha-7 receptor and AMPA receptor positive allosteric modulators (PAM) are also potential substances in this context. Our objective is to evaluate the effects of caffeine, modafinil, AVL-3288 (nicotinic alpha-7 PAM) and CX516 (AMPA receptor PAM) on cognition and mood in a model of sleep deprivation.METHODModified multiple platform model is used to sleep-deprive mice for 24 days, for 8 h/day. Vehicle, Modafinil (40 mg/kg), Caffeine (5 mg/kg), CX516 (10 mg/kg), and AVL3288 (1 mg/kg) were administered intraperitoneally daily. A cognitive test battery was applied every six days for four times. The battery that included elevated plus maze, novel object recognition, and sucrose preference tests was administered on consecutive days.RESULTSSleep deprivation decreased novel object recognition skill, but no significant difference was found in anxiety and depressive mood. Caffeine administration decreased anxiety-like behavior in short term, but this effect disappeared in chronic administration. Caffeine administration increased memory performance in chronic period. AVL group showed better memory performance in short term, but this effect disappeared in the rest of experiment. Although, in the modafinil group, no significant change in mood and memory was observed, anhedonia was observed in the chronic period in vehicle, caffeine and modafinil groups, but not in AVL-3288 and CX-516 groups.CONCLUSIONCaffeine has anxiolytic effect in acute administration. The improvement of memory in chronic period may be associated with the neuroprotective effects of caffeine. AVL-3288 had a short-term positive effect on memory, but tolerance to these effects developed over time. Furthermore, no anhedonia was observed in AVL-3288 and CX516 groups in contrast to vehicle, caffeine and modafinil groups. This indicates that AVL-3288 and CX516 may show protective effect against depression.

01 Feb 2024·Experimental Neurology

Enhancing cognitive function in chronic TBI: The Role of α7 nicotinic acetylcholine receptor modulation

Article

Author: Placeres-Uray, Fabiola ; Gee, Kelvin W ; Johnstone, Timothy ; Hogenkamp, Derk ; Titus, David J ; Atkins, Coleen M ; Sangadi, Dinesh K ; Sangadi, Akhila

Traumatic brain injury (TBI) results in several pathological changes within the hippocampus that result in adverse effects on learning and memory. Therapeutic strategies to enhance learning and memory after TBI are still in the early stages of clinical development. One strategy is to target the α7 nicotinic acetylcholine receptor (nAChR), which is highly expressed in the hippocampus and contributes to the formation of long-term memory. In our previous study, we found that AVL-3288, a positive allosteric modulator of the α7 nAChR, improved cognitive recovery in rats after moderate fluid-percussion injury (FPI). However, whether AVL-3288 improved cognitive recovery specifically through the α7 nAChR was not definitively determined. In this study we utilized Chrna7 knockout mice and compared their recovery to wild-type mice treated with AVL-3288 after TBI. We hypothesized that AVL-3288 treatment would improve learning and memory in wild-type mice, but not Chrna7^-/- mice after TBI. Adult male C57BL/6 wild-type and Chrna7^-/- mice received sham surgery or moderate controlled cortical impact (CCI) and recovered for 3 months. Mice were then treated with vehicle or AVL-3288 at 30 min prior to contextual fear conditioning. At 3 months after CCI, expression of α7 nAChR, choline acetyltransferase (ChAT), high-affinity choline transporter (ChT), and vesicular acetylcholine transporter (VAChT) were found to be significantly decreased in the hippocampus. Treatment of wild-type mice at 3 months after CCI with AVL-3288 significantly improved cue and contextual fear conditioning, whereas no beneficial effects were observed in Chrna7^-/- mice. Parietal cortex and hippocampal atrophy were not improved with AVL-3288 treatment in either wild-type or Chrna7^-/- mice. Our results indicate that AVL-3288 improves cognition during the chronic recovery phase of TBI through modulation of the α7 nAChR.

01 Jul 2020·NeuropsychopharmacologyQ1 · MEDICINE

Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients

Q1 · MEDICINE

Article

Author: Wall, Melanie M ; Kantrowitz, Joshua T ; Freedman, Robert ; Sobeih, Tarek ; Vail, Blair ; Sehatpour, Pejman ; Kegeles, Lawrence S ; Carlson, Marlene ; Choo, Tse-Hwei ; Lieberman, Jeffrey A ; Javitt, Daniel C ; Grinband, Jack

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα₇) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα₇ positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα₇ target.

100 Deals associated with AVL-3288

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cognitive Dysfunction	Preclinical	-	University of Maryland Baltimore	01 May 2018
Central Nervous System Diseases	Preclinical	US	University of California, Irvine	08 May 2007
Schizoaffective disorder	Discovery	US	National Institute of Mental Health	01 Nov 2016
Schizophrenia	Discovery	US	National Institute of Mental Health	01 Nov 2016
Cognition Disorders	Discovery	-	Anvyl Pharmaceuticals	-
Cognition Disorders	Discovery	US	Anvyl LLC	-