tcsc0933 Encenicline

Encenicline (EVP-6124) is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs).

IC50 & Target: α7 nAChR^[1]

In Vitro: Encenicline (EVP-6124) displaces [³H]-MLA (Methyllycaconitine) (K_i=9.98 nM, pIC₅₀=7.65±0.06, n=3) and [¹²⁵I]-α-bungarotoxin (K_i=4.33 nM, pIC₅₀=8.07±0.04, n=3). Encenicline (EVP-6124) is approximately 300 fold more potent than the natural agonist ACh (K_i=3 μM), measured in binding assays using [³H]-MLA. Encenicline inhibits the 5-HT₃ receptor by 51% at 10 nM, the lowest concentration tested. Evaluation of the human 5-HT_2B receptor expressed in CHO cells demonstrates displacement of [³H]-mesulergine (K_i=14 nM) and only antagonist activity in the rat gastric fundus assay at an IC₅₀ of 16 μM. In binding and functional experiments, Encenicline shows selectivity for α7 nAChRs and does not activate or inhibit heteromeric α4β2 nAChRs^[1].

In Vivo: Encenicline (EVP-6124) has good brain penetration and an adequate exposure time. Encenicline (EVP-6124) (0.3 mg/kg, p.o.) significantly restores memory function in scopolamine-treated rats (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or Encenicline at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time, Encenicline improved memory at 0.3 mg/kg, p.o. This improvement is blocked by the selective α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 μg, i.c.v.). Encenicline (EVP-6124) is found to bind moderately to rat plasma proteins with a mean fu of 0.11±0.01 (mean±SD) or 11%. Over a range of 0.1-30 mg/kg, p.o., Encenicline (EVP-6124) demonstrates proportional dose escalation. T_max is at 4 h in plasma and 2 h brain, although the brain concentrations remained similar between 2 and 8 h. The B:P ratios are 1.7-5.1 between 1 and 8 h^[1]. Pharmacokinetic studies have shown that Encenicline (EVP-6124) (0.4 mg/kg, i.p.) reaches peak brain concentration 2 hr after administration and remains at effective concentrations for at least 4 hr. Encenicline (EVP-6124) is administered to WT mice at ZT0 (0.4 mg/kg i.p single dose) and significantly increases the saturation index of NMDARs in slices obtained 4 hr later without causing prolonged wakefulness or enhanced locomotor activity ^[2].