NLX-112, a highly selective 5-HT 1A receptor agonist: Effects on body temperature and plasma corticosterone levels in rats

NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translat...

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Published inPharmacology, biochemistry and behavior Vol. 165; p. 56
Main Authors Newman-Tancredi, A, Depoortère, R, Carilla-Durand, E, Tarayre, J P, Kleven, M, Koek, W, Bardin, L, Varney, M A
Format Journal Article
LanguageEnglish
Published United States 01.02.2018
Subjects
Animals
Biomarkers - blood
Body Temperature - drug effects
Corticosterone - blood
Dose-Response Relationship, Drug
Hypothermia - blood
Hypothermia - chemically induced
Male
Piperazines - pharmacology
Piperidines - pharmacology
Pyridines - pharmacology
Rats, Sprague-Dawley
Serotonin 5-HT1 Receptor Agonists - pharmacology
5-HT(1A) receptors
Biomarker
Serotonin
Corticosterone
Befiradol
Hypothermia
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Summary:NLX-112 (a.k.a. F13640 or befiradol), exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine 5-HT receptors. It possesses marked activity in a variety of animal models of depression, pain and L-DOPA-induced dyskinesia. However, its influence on translational biomarkers of central 5-HT receptor activation has not been previously described. Here, we report on the activity, in rats, of NLX-112 to increase plasma corticosterone levels and produce hypothermia, two responses which are also elicited by 5-HT receptor agonists in humans. NLX-112 elicited dose-dependent hypothermia (minimal effective dose, MED: 0.31mg/kg p.o.) and also increased plasma corticosterone both by oral and intraperitoneal routes (MED: 0.63mg/kg in both cases). The increase in corticosterone induced by NLX-112 (0.63mg/kg p.o.) was abolished by co-administration of the selective 5-HT receptor antagonist, WAY100635. Additionally, NLX-112 also dose-dependently induced flat body posture, forepaw treading and lower lip retraction (MEDs 0.31-0.63mg/kg p.o.). The doses of NLX-112 which induce hypothermia or corticosterone release were similar to those inducing serotonergic behaviors but greater than those reported previously in models of therapeutic-like activity (range 0.04 to 0.16mg/kg). Overall, the present study provides information for clinical dose estimations of NLX-112 and suggests that therapeutic effects may occur at doses below those at which biomarker responses are observed.
ISSN:1873-5177