Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites

Abstract

A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group. Potent agonists were identified, including some with a mGlu subtype preference, e.g., 17m (LSP1-2111) and 16g (LSP4-2022). Molecular modeling suggests that aromatic functional groups may bind at either one of the two chloride regulatory sites. These agonists may thus be considered as particular bitopic/dualsteric ligands. 17m was shown to reduce GABAergic synaptic transmission at striatopallidal synapses. We now demonstrate its inhibitory effect at glutamatergic parallel fiber-Purkinje cell synapses in the cerebellar cortex. Although these ligands have physicochemical properties that are markedly different from typical CNS drugs, they hold significant therapeutic potential.

Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

“…Interestingly, this approach is also valid for other mGluRs. For example, the first mGlu4 receptor selective orthosteric agonist named LSP4-2022 is a dualsteric/bitopic ligand targeting both the glutamate-and the Clbinding pockets of the mGlu4 receptor (Goudet et al, 2012;Selvam et al, 2018). Hopefully, new selective ligands will help to better define the particular roles of mGlu3 receptors.…”

The Role of the Phosphorus Atom in Drug Design

“…The epimeric mixture of 162 at the benzylic carbon, known as LSP1‐2111, is a Group III mGluR agonist with preference for mGluR4 and is used mostly to study the behavioral pharmacology of mGluR4 activation, particularly via orthosteric agonist mechanisms . Compound 162 , which contains the structure of 159 , is a very interesting compound acting as an effective and selective dual‐steric/bitopic ligand of Group III mGluRs, and inhibits glutamate or GABA release through stimulation of presynaptic mGluR4 . Notably, 162 and other closely related compounds are very polar, and so their physicochemical properties are not those required for central nervous system drugs .…”

“…[149] Notably, 162 and other closely related compounds are very polar,a nd so their physicochemical properties are not those required for central nervous system drugs. [149] Despite this fact, this class of molecules offersg reat potential for pharmacological use.…”

Metabotropic Glutamate Receptor 7: A New Therapeutic Target in Neurodevelopmental Disorders

“…Many in vitro and in vivo studies examining the effects of mGlu 7 potentiation have been performed with orthosteric Group III mGlu agonists such as L-2-amino-4-phosphonobutyric acid (L-AP4, 1 ), LSP4-2022 ( 2 ), and LSP1-2111 ( 3 ). L-AP4 exhibits an in vitro potency (EC 50 ) of 0.1, 337, and 0.29 μM at mGlu 4 , mGlu 7 , and mGlu 8 , respectively ( Acher et al, 2012 ; Selvam et al, 2018 ). Similarly, LSP4-2022 exhibits in vitro EC 50s of 0.11, 11.6, and 29.2 μM at mGlu 4 , mGlu 7 , and mGlu 8 , respectively ( Acher et al, 2012 ; Goudet et al, 2012 ; Selvam et al, 2018 ), while a structurally-related analog, LSP1-2111, displays EC 50s of 2.2, 53, and 66 μM at each of these receptors ( Selvam et al, 2018 ).…”