Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor

Compounds modulating metabotropic glutamate type 2 ( mGlu2 ) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological and pharmacokinetic properties of a novel mGlu2 receptor‐positive allosteric modulator (PAM), 1‐butyl‐3‐chloro‐4‐(4‐phenyl‐1‐piperidinyl)‐2(1 H )‐pyridinone (JNJ‐40411813/ADX71149) are described here. JNJ‐40411813 acts as a PAM at the cloned mGlu2 receptor: EC 50  = 147 ± 42 nmol/L in a [ 35 S]GTP γ S binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC 50  = 64 ± 29 nmol/L in a Ca 2+ mobilization assay with hmGlu2 G α 16 cotransfected HEK293 cells. [ 35 S]GTP γ S autoradiography on rat brain slices confirmed PAM activity of JNJ‐40411813 on native mG lu2 receptor. JNJ‐40411813 displaced [ 3 H]JNJ‐40068782 and [ 3 H]JNJ‐46281222 ( mG lu2 receptor PAMs), while it failed to displace [ 3 H]LY341495 (a competitive mG lu2/3 receptor antagonist). In rats, JNJ‐40411813 showed ex vivo mG lu2 receptor occupancy using [ 3 H]JNJ‐46281222 with ED 50 of 16 mg/kg (p.o.). PK‐PD modeling using the same radioligand resulted in an EC 50 of 1032 ng/mL. While JNJ‐40411813 demonstrated moderate affinity for human 5HT 2A receptor in vitro ( K b  = 1.1  μ mol/L), higher than expected 5HT 2A occupancy was observed in vivo (in rats, ED 50  = 17 mg/kg p.o.) due to a metabolite. JNJ‐40411813 dose dependently suppressed REM sleep ( LAD , 3 mg/kg p.o.), and promoted and consolidated deep sleep. In fed rats, JNJ‐40411813 (10 mg/kg p.o.) was rapidly absorbed ( C max 938 ng/mL at 0.5 h) with an absolute oral bioavailability of 31%. Collectively, our data show that JNJ‐40411813 is an interesting candidate to explore the therapeutic potential of mGlu2 PAM s, in in vivo rodents experiments as well as in clinical studies.