NLX-112, a highly selective 5-HT 1A receptor biased agonist, does not exhibit misuse potential in male rats or macaques.

Autor: Depoortère R; Neurolixis SAS, 2 rue Georges Charpak, 81100, Castres, France. Electronic address: rdepoortere@neurolixis.com., Bergman J; McLean Hospital, Behavioral Biology Program, Belmont, MA, 02478, USA., Beardsley PM; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA; Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA., Desai RI; McLean Hospital, Behavioral Biology Program, Belmont, MA, 02478, USA., Paronis CA; McLean Hospital, Behavioral Biology Program, Belmont, MA, 02478, USA., Walentiny DM; Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, 23298-0613, USA., Varney MA; Neurolixis SAS, 2 rue Georges Charpak, 81100, Castres, France., Newman-Tancredi A; Neurolixis SAS, 2 rue Georges Charpak, 81100, Castres, France.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2022 Jun 01; Vol. 210, pp. 109025. Date of Electronic Publication: 2022 Mar 09.
DOI: 10.1016/j.neuropharm.2022.109025
Abstrakt: NLX-112 (a.k.a. F13640 or befiradol) exhibits nanomolar affinity, exceptional selectivity and biased agonism at serotonin 5-HT 1A receptors. NLX-112 displays robust analgesic activity in a number of rodent models of pain, and is currently developed as a treatment for l-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD) patients. Noteworthy, PD patients can suffer from comorbid chronic pain, thus necessitating the use of analgesic drugs, such as opioids, which have potential for misuse. Additionally, dopamine agonists used to treat PD can produce cocaine-like effects in preclinical assays of misuse potential. The present study investigated whether NLX-112 possesses misuse potential of its own using two behavioural assays routinely used for this purpose: intracranial self-stimulation (ICSS) in rats, and cocaine discrimination in macaque monkeys. In rats, low doses of NLX-112 (0.03 and 0.1 mg/kg p.o.) did not alter ICSS frequency-rate curves, while higher doses (0.3 and 1.0 mg/kg) shifted the curve to the right and flattened it, i.e., reduced ICSS. As expected, cocaine (10 mg/kg i.p.) shifted the curve to the left, i.e., facilitated ICSS, but NLX-112 (0.03 and 0.1 mg/kg p.o.) did not further enhance cocaine-induced facilitation of ICSS. In monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) from saline, NLX-112 (0.01-0.1 mg/kg p.o.) did not substitute for cocaine. Taken together, these results suggest that NLX-112, at doses displaying anti-dyskinetic activity in rat, marmoset and macaque models of LID, is free from misuse potential. From a translational perspective, this is a desirable property for a compound destined to be used in PD patients, who can suffer from comorbid chronic pain necessitating the use of potentially misused analgesic drugs.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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