title: Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor.
abstract: 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(1H)-pyridinone (JNJ-40411813/ADX71149) are described here. JNJ-40411813 acts as a PAM at the cloned mGlu2 receptor: EC50 = 147 ± 42 nmol/L in a [(35)S]GTPγS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 ± 29 nmol/L in a Ca(2+) mobilization assay with hmGlu2 G α16 cotransfected HEK293 cells. [(35)S]GTPγS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [(3)H]JNJ-40068782 and [(3)H]JNJ-46281222 (mGlu2 receptor PAMs), while it failed to displace [(3)H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [(3)H]JNJ-46281222 with ED50 of 16 mg/kg (p.o.). PK-PD modeling using the same radioligand resulted in an EC50 of 1032 ng/mL. While JNJ-40411813 demonstrated moderate affinity for human 5HT2A receptor in vitro (K b = 1.1 μmol/L), higher than expected 5HT2A occupancy was observed in vivo (in rats, ED50 = 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 PAMs, in in vivo rodents experiments as well as in clinical studies.
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Ahnaou
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.affiliation: Janssen Research & Development, Janssen Pharmaceutica NV Beerse, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pype
authors.affiliation: Addex Therapeutics Geneva, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Lütjens
authors.affiliation: Addex Therapeutics Geneva, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Poul
authors.affiliation: Janssen Research & Development, Janssen-Cilag Toledo, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: Janssen Research & Development, Janssen-Cilag Toledo, Spain.
authors.forename: José María Cid
authors.initials: JM
authors.lastname: Nuñez
keywords: In vitro; JNJ-40411813; mGlu2 PAM; occupancy; pharmacokinetics; sleep–wake EEG