ADX88178 / National Institute on Drug Abuse, Addex - LARVOL DELTA

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia. (PubMed, J Parkinsons Dis) - "Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated...We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R) N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia...This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Effect of ADX-88178, a highly-selective mGlu4 PAM, on parkinsonism, dyskinesia and psychosis-like behaviours in the MPTP-lesioned marmoset (MDS Congress 2023) - "Recently, the development of the mGlu PAM foliglurax was discontinued, after it failed to meet endpoints pertaining to off time and dyskinesia in a clinical trial...ADX-88178 is a highly-selective mGlu PAM that previously reversed catalepsy induced by haloperidol in the rat and enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat... These results provide additional evidence of the anti-parkinsonian effect of ADX-88178 as an adjunct to L-DOPA and also indicate that ADX-88178 may alleviate L-DOPA-induced dyskinesia. However, they also suggest that ADX-88178 may not be suitable for PD patients with psychotic manifestations; whether it is a drug-specific or a class effect warrants further investigation."

CNS Disorders • Parkinson's Disease • Psychiatry

Effect of the mGlu positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset. (PubMed, Psychopharmacology (Berl)) - "Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu PAMs on PD psychosis."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties. (PubMed, J Enzyme Inhib Med Chem) - "Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu PAM ADX88178."

Journal • CNS Disorders

Putative mGluR4 Positive Allosteric Modulators Activate G-Independent Anti-Inflammatory Mechanisms in Microglia. (PubMed, Neurochem Int) - "Other mGluR4 modulators had divergent activities; VU0361737 (PAM) showed anti-inflammatory effects, whereas the orthosteric group III agonist, L-AP4, and VU0155041 (PAM) displayed no anti-inflammatory actions. ADX88178 did not exert its anti-inflammatory effects through adenosine receptors, reported as mGluR4 heteromerization partners. Thus, our results indicate that in microglia, putative mGluR4 PAMs activate mGluR4/G-independent mechanisms to attenuate pro-inflammatory pathways."

Journal • CNS Disorders • Immunology • Infectious Disease • CCL2 • IL6 • miR-155

Characterization of the novel positive allosteric modulator of mGlu4 receptor Characterization of the novel positive allosteric modulator of mGlu4 receptor ADX88178 in rodent models of neuropsychiatric disorders (J Pharmacol Exp Ther) - "ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of anti-depressant like efficacy. ADX88178 reduced DOI-mediated head twitches (albeit with no dose-dependency) and MK-801-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses."

Preclinical • Parkinson's Disease

Characterization of a mGlu4 positive allosteric modulator by telemetric EEG/ECG recordings and sociability assessment in freely moving rats (ECNP 2019) - "...Thus mGlu4 modulation may demonstrate an attractive therapeutic target in psychiatric drug discovery to counteract the growing unmet medical need.Objective:In the present study we investigated a commercially available mGlu4PAM (ADX-88178 [2]) by taking advantage of telemetric EEG/ECG-recordings to reveal pharmacological induced alterations in power spectra, sleep-wake architecture, and behaviour as functional readout...The investigated mGlu4PAM revealed a high level of central target engagement. HRV analysis revealed its peripheral effects with an increased sympathetic response and thus an alteration in the parasympathetic/sympathetic balance of the autonomous nervous system. The behavioural assessment may indicate an increment in exploratory behaviour and a procognitive impact as only 10 and 30 mg/kg mGlu4PAM elicited social recognition discrimination between the two social stimuli."

Preclinical