Encenicline demonstrates efficient brain penetration and maintains an adequate exposure duration. When administered orally at 0.3 mg/kg, it significantly reverses memory deficits induced by scopolamine (0.1 mg/kg, i.p.) in rats during an object recognition task (ORT). Although neither donepezil (at 0.1 mg/kg, p.o.) nor Encenicline (at 0.03 mg/kg, p.o.) alone enhances memory in this task, their combination restores memory effectively. Moreover, at 0.3 mg/kg, p.o., Encenicline improves memory in an ORT with a 24-hour retention period, an effect blocked by the selective α7 nAChR antagonist methyllycaconitine. Encenicline binds moderately to rat plasma proteins, exhibiting a fractional unbound value of approximately 11%. Dose escalation from 0.1-30 mg/kg, p.o., is proportional, with Tmax observed at 4 hours in plasma and 2 hours in the brain, where concentration levels remain steady for up to 8 hours^[1].

Pharmacokinetic evaluations reveal that Encenicline, at 0.4 mg/kg, i.p., reaches its peak brain concentration 2 hours post-administration and sustains effective levels for at least 4 hours. Administered to WT mice, a single dose of Encenicline (0.4 mg/kg, i.p.) at ZT0 significantly elevates the NMDAR saturation index in brain slices obtained 4 hours later without inducing prolonged wakefulness or increased locomotor activity^[2].

Encenicline (EVP-6124) effectively competes with [³H]-MLA (Methyllycaconitine) and [¹²⁵I]-α-bungarotoxin for binding, showing Ki values of 9.98 nM and 4.33 nM, respectively. This highlights its roughly 300-fold greater potency than the natural agonist ACh (acetylcholine), which has a Ki of 3 μM in assays involving [³H]-MLA. At a minimal concentration of 10 nM, Encenicline achieves a 51% inhibition of the 5-HT3 receptor. Further, it displaces [³H]-mesulergine from the human 5-HT2B receptor expressed in CHO cells with a Ki of 14 nM and displays only antagonist activity in the rat gastric fundus assay, indicating an IC50 of 16 μM. Notably, Encenicline exhibits a preference for α7 nicotinic acetylcholine receptors (nAChRs) without affecting the heteromeric α4β2 nAChRs in both binding and functional tests^[1].