NLX-112 (a.k.a.
F13640 or
befiradol) exhibits nanomolar affinity, exceptional selectivity and biased agonism at
serotonin 5-HT1A 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.