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 [35S]GTPγS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 ± 29 nmol/L in a Ca2+ mobilization assay with hmGlu2 Gα16 cotransfected HEK293 cells. [35S]GTPγS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [3H]JNJ-40068782 and [3H]JNJ-46281222 (mGlu2 receptor PAMs), while it failed to displace [3H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [3H]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 (Kb = 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 (Cmax 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.
Highlights
Among the metabotropic glutamate receptors, metabotropic glutamate type 2 (mGlu2), an inhibitory presynaptic autoreceptor, has emerged as a novel therapeutic target for the treatment of psychiatric disorders including schizophrenia, depression and anxiety, which are characterized by glutamatergic dysfunction (Marek et al 2010; Riaza Bermudo-Soriano et al 2012; Sanacora et al 2012).Testing of selective mGlu2/3 receptor agonists in animal studies involving N-methyl-D-aspartate (NMDA) receptor antagonists like phencyclidine (PCP) provided a 2014 The Authors
JNJ-40411813 acts as a positive allosteric modulator (PAM) at the cloned mGlu2 receptor: EC50 = 147 Æ 42 nmol/L in a [35S]GTPcS binding assay with human metabotropic glutamate type 2 Chinese hamster ovary (CHO) cells and EC50 = 64 Æ 29 nmol/L in a Ca2+ mobilization assay with hmGlu2 Ga16 cotransfected HEK293 cells. [35S]GTPcS autoradiography on rat brain slices confirmed PAM activity of JNJ40411813 on native mGlu2 receptor
Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics
Summary
Among the metabotropic glutamate (mGlu) receptors, mGlu, an inhibitory presynaptic autoreceptor, has emerged as a novel therapeutic target for the treatment of psychiatric disorders including schizophrenia, depression and anxiety, which are characterized by glutamatergic dysfunction (Marek et al 2010; Riaza Bermudo-Soriano et al 2012; Sanacora et al 2012).Testing of selective mGlu2/3 receptor agonists in animal studies involving N-methyl-D-aspartate (NMDA) receptor antagonists like phencyclidine (PCP) provided a 2014 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics Pharmacology and Pharmacokinetics of JNJ-40411813 early evidence that mGlu2/3 receptors may represent a novel target for schizophrenia treatment. Both LY354740 and LY379268, potent orthosteric mGlu2/3 agonists, inhibit PCP-evoked increases in glutamate levels and PCPinduced hyperlocomotion in rats (Moghaddam and Adams 1998; Cartmell et al 1999). The improvements in schizophrenia-related symptoms were not confirmed in subsequent follow-up trials (Kinon et al 2011; Stauffer et al 2013), and it is questioned whether only particular symptoms or disease stages exhibit a glutamatergic-based origin (Goff and Coyle, 2001; Marsman et al, 2013), and whether earlier results can be generalized to the broader population of patients with schizophrenia or whether these are specific only to subpopulations of patients
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