Synthesis and Metabotropic Glutamate Receptor Activity of S-Oxidized Variants of (−)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate:  Identification of Potent, Selective, and Orally Bioavailable Agonists for mGlu2/3 Receptors

Abstract

(-)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-3) is a highly potent and selective agonist of metabotropic glutamate receptors 2 (mGlu2) and 3 (mGlu3). As part of our ongoing research program, we have prepared S-oxidized variants of (-)-3, compounds (-)-10, (+)-11 (LY404040), and (-)-12 (LY404039). Each of these chiral heterobicyclic amino acids displaced specific binding of the mGlu2/3 receptor antagonist 3H-2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (3H-LY341495) from membranes expressing recombinant human mGlu2 or mGlu3 and acted as potent agonists in cells expressing these receptor subtypes. Docking of the most potent of these derivatives, (+)-11, to mGlu2 revealed the possibility of an additional H-bond interaction between the sulfoxide oxygen of (+)-11 with tyrosine residue Y236. Pharmacokinetic analysis of mGlu active enantiomers (+)-11 and (-)-12 in rats showed each to be well absorbed following oral administration. Consistent with their mGlu2/3 agonist potency and pharmacokinetic properties, both (+)-11 and (-)-12 blocked phencyclidine-evoked ambulations in a dose-dependent manner, indicating their potential as nonclassical antipsychotic agents.

Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (–)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039)

“…We report here that LY404039 effectively modulates mGlu2/3 receptors in situ with a potency similar to that previously reported for LY354740, suggesting that this compound should also demonstrate efficacy in animal models of psychosis and anxiety. Perhaps most importantly, we demonstrate here that despite the in vitro similarities between LY354740 and LY404039, oral administration of LY404039 results in much higher plasma levels and bioavailability (63%; Monn et al, 2007) than previously observed following oral administration of LY354740 (ϳ10%; Johnson et al, 2002) and a different pharmacokinetic profile. The mechanism by which LY404039 crosses the gastrointestinal tract is not clearly understood.…”

“…Interestingly, although similar to LY354740, LY404039 was ϳ2-to 3-fold less potent in this assay. Despite the slightly lower potency of LY404039 versus LY354740 in binding and functional assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments in rats [ϳ63% (see Monn et al, 2007) compared with ϳ10% for LY354740 (Johnson et al, 2002)]. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, an effect reversed by the mGlu2/3 receptor antagonist LY341495, indicating that the suppression of neural activity was probably mediated via mGlu2/3 receptors.…”

“…Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of the structurally novel mGlu2/3 receptor agonist (Ϫ)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) (Fig. 1) (Monn et al, 2007) and provide comparisons with LY354740. We characterize the efficacy, potency, and selectivity of LY404039 and LY354740 at human and rat mGlu and iGlu receptors as well as binding at glutamate transporters and receptors implicated in the efficacy of current anxiolytic and antipsychotic medications, including adrenergic, monoaminergic, and GABAergic receptors.…”

Evidence for the Role of Metabotropic Glutamate (mGlu)2 Not mGlu3 Receptors in the Preclinical Antipsychotic Pharmacology of the mGlu2/3 Receptor Agonist (–)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic Acid (LY404039)

“…The amino acid analog LY404039 (Monn et al, 2007) is a potent and highly selective agonist for group II mGlu receptors, and it has no appreciable affinity for group I or group III mGlu receptors, ionotropic glutamate receptors, glutamate transporters, or other receptors such as dopamine and serotonin (Rorick-Kehn et al, 2007a). Like atypical antipsychotics (e.g., clozapine and olanzapine), LY404039 displays antipsychotic-like effects in animal models of psychosis.…”

“…Like atypical antipsychotics (e.g., clozapine and olanzapine), LY404039 displays antipsychotic-like effects in animal models of psychosis. LY404039 reverses phencyclidine (PCP)-induced hyperlocomotion in rats in a dose-dependent manner (Monn et al, 2007;Rorick-Kehn et al, 2007b). Although LY404039 has no affinity at dopamine receptors, it attenuates the locomotorstimulating effects of d-amphetamine (AMP).…”