Synthesis and Pharmacological Characterization of 4-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: Identification of New Potent and Selective Metabotropic Glutamate 2/3 Receptor Agonists

Abstract

As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo.

The anatomy of mammalian sweet taste receptors

“…S1 and S2) and contributes to understanding the ligand–receptor interactions involved in the recognition of sweeteners by T1R2 and T1R3. Similar to what is observed in X‐Ray structures of mGluR VFDs, the binding cavities for sweet compounds are located in between the T1R2 and T1R3 lobes (Fig. ).…”

Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors

“…Because S152 and D146 do not directly interact with agonists (Muto et al, 2007), our results suggest that this affinity reversal was due to an arginine flip that alters the conformation of more proximal tyrosine. Furthermore, a new, selective mGlu2 receptor agonist has been proposed to bind near S278/S272 (Monn et al, 2013), directly adjacent to R277/R271 at mGlu3 and mGlu2 receptors, respectively. Because our models do not predict different conformations of S278 and S272, the selective mGlu2 receptor agonist may actually exploit different conformations of the neighboring tyrosine and/or arginine residues.…”

Synthesis of complex unnatural fluorine-containing amino acids

“…The synthesis of 4-fluoro-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 108 was reported by Monn and co-workers in 2013 for the purpose of carrying out biological studies ( Scheme 24 ) [ 95 ]. Initial reduction of ketone 105 , a versatile intermediate prepared from enone 103 [ 96 ], resulted in the formation of β-carbinol 106 [ 97 ].…”

“…Various attempts to synthesise the β-fluoro analogue proved largely unsuccessful as only trace amounts of the desired compound were salvaged from the crude material.

Scheme 24 Synthesis of 4-fluoro-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate, Monn and co-workers [ 95 ].

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