Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor. Issue 1 (9th December 2014)

• Record Type: Journal Article
• Authors: Lavreysen, Hilde; Ahnaou, Abdellah; Drinkenburg, Wilhelmus; Langlois, Xavier; Mackie, Claire; Pype, Stefan; Lütjens, Robert; Le Poul, Emmanuel; Trabanco, Andrés A.; Nuñez, José María Cid
• Is Part Of: Pharmacology research & perspectives. Volume 3:Issue 1(2015:Feb.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2014-12-09
• Subjects: Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.96
• Languages: English
• ISSNs: 2052-1707

Abstract

<abstract abstract-type="main" id="prp296-abs-0001"> <title>Abstract</title> <p>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<italic>H</italic>)‐pyridinone (JNJ‐40411813/ADX71149) are described here. JNJ‐40411813 acts as a PAM at the cloned mGlu2 receptor: EC<sub>50</sub> = 147 ± 42 nmol/L in a [<sup>35</sup>S]GTP<italic>γ</italic>S binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC<sub>50</sub> = 64 ± 29 nmol/L in a Ca<sup>2+</sup> mobilization assay with hmGlu2 G<sub><italic>α</italic>16</sub> cotransfected HEK293 cells. [<sup>35</sup>S]GTP<italic>γ</italic>S autoradiography on rat brain slices confirmed PAM activity of JNJ‐40411813 on native mGlu2 receptor. JNJ‐40411813 displaced [<sup>3</sup>H]JNJ‐40068782 and [<sup>3</sup>H]JNJ‐46281222 (mGlu2 receptor PAMs), while it failed to displace [<sup>3</sup>H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ‐40411813 showed ex vivo mGlu2 receptor occupancy using [<sup>3</sup>H]JNJ‐46281222 with ED<sub>50</sub> of 16 mg/kg (p.o.). PK‐PD modeling using the same radioligand resulted in an EC<sub>50</sub> of 1032 ng/mL. While JNJ‐40411813 demonstrated moderate affinity for human 5HT<sub>2A</sub> receptor in vitro (<italic>K</italic><sub>b</sub> = 1.1 <italic>μ</italic>mol/L), higher than expected 5HT<sub>2A</sub> occupancy was observed in vivo (in rats, ED<sub>50</sub> = 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 (<italic>C</italic><sub>max</sub> 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.</p> </abstract>