Abstract
Activation of metabotropic glutamate receptor subtype 5 (mGlu5) represents a novel strategy for therapeutic intervention into multiple central nervous system (CNS) disorders including schizophrenia. Recently, a number of positive allosteric modulators (PAMs) of mGlu5 have been discovered to exhibit in vivo efficacy in rodent models of psychosis, including PAMs possessing varying degrees of agonist activity (ago-PAMs) as well as PAMs devoid of agonist activity. However, previous studies revealed that ago-PAMs can induce seizure activity and behavioral convulsions, whereas pure mGlu5 PAMs do not induce these adverse effects. We recently identified a potent and selective mGlu5 PAM, VU0403602, which was efficacious in reversing amphetamine-induced hyperlocomotion in rats. The compound also induced time-dependent seizure activity that was blocked by co-administration of the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine (MPEP). Consistent with potential adverse effects induced by ago-PAMs, we found that VU0403602 had significant allosteric agonist activity. Interestingly, inhibition of VU0403602 metabolism in vivo by a pan P450-inactivator completely protected rats from induction of seizures. P450-mediated biotransformation of VU0403602 was discovered to produce another potent ago-PAM metabolite-ligand (M1) of mGlu5. Electrophysiological studies in rat hippocampal slices confirmed agonist activity of both M1 and VU0403602 and revealed that M1 can induce epileptiform activity in a manner consistent with its pro-convulsant behavioral effects. Furthermore, unbound brain exposure of M1 was similar to that of the parent compound VU0403602. These findings indicate that biotransformation of mGlu5 PAMs to active metabolite-ligands may contribute to the epileptogenesis observed following in vivo administration of this class of allosteric receptor modulators.
- adverse drug reactions
- CNS pharmacokinetics
- drug disposition
- drug distribution
- metabolite identification
- metabolite kinetics
- neurotoxicity
- structure-activity relationships
- The American Society for Pharmacology and Experimental Therapeutics