NLX-101 (F-15599)

Biological Activity

NLX-101 (F-15599) is a highly selective G-protein biased 5-HT1A receptor agonist, with Ki of 3.4 nM. NLX-101 (F-15599) mediates antidepressant-like activity in rats via prefrontal cortex 5-HT 1A receptors. NLX-101 (F-15599) has over 1000-fold higher affinity for this target over other receptors. 

F15599 (0.06 or 0.12 mg/kg) significantly reduces l-DOPA-induced dyskinesia (LID). F15599 (0.0625, 0.125, 0.25, 0.5 and 1.0 mg/kg, i,p,) results in a significant and dose-dependent (MED = 0.125 mg/kg) delay in the latency to attack, and a potent reduction (ID50 = 0.095 mg/kg) in the amount of aggressive behaviour directed towards the intruder rat. Starting from the 0.25 mg/kg dose, F15599 induces clear signs of the so-called serotonin syndrome characterized by flat body posture, head-waving, lower lip retraction and hindlimb abduction, leading to increased behavioural inactivity scores and social disengagement. F15599 increases dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 µg/kg i.p., whereas it reduces hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 µg/kg i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] R Depoortere, et al. Behav Brain Res. NLX-101, a highly selective 5-HT 1A receptor biased agonist, mediates antidepressant-like activity in rats via prefrontal cortex 5-HT 1A receptors

[2] Samantha M Meadows, et al. Exp Neurol. Characterizing the differential roles of striatal 5-HT 1A auto- and hetero-receptors in the reduction of l-DOPA-induced dyskinesia

[3] Sietse F de Boer, et al. Psychopharmacology (Berl). Anti-aggressive effects of the selective high-efficacy 'biased' 5-HT₁A receptor agonists F15599 and F13714 in male WTG rats

[4] Philippe Huot, et al. Neuropharmacology. The highly-selective 5-HT(1A) agonist F15599 reduces L-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque

[5] L Llado-Pelfort, et al. Br J Pharmacol. Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors