Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.

Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family

“…We carried out the 100 ns MD simulations for the mGluR5 (residue 26-832, formed by Venus Flytrap domain, a so-called cysteine-rich domain, and 7 trans-membrane domains) bound with (a) antagonist-LY-344545 (65) (an epimer of LY-341495, mGluR2/3 selective antagonist) and NAM-mavoglurant (28) and (b) agonist-glutamate and PAM-VU0405386 (53). The original binding pose of agonistglutamate in mGluR5 was the same as it was in the crystal structures (mGluR5 complexes with glutamate-PDB entry: 3LMK), as shown in Fig.…”

VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy

“…We searched our available mGlu 5 allosteric antagonists to identify novel compounds with weak negative cooperativity. In screening compounds within the picolinamide acetylene class series (Stauffer, 2011;Bridges et al, 2013;Turlington et al, 2013;, we noted that the mGlu 5 NAM VU0477573 (C 18 ,H 17 ,FN 2 O; molecular weight 5 296.34) showed limited negative cooperativity in inhibiting the glutamate EC 80 -induced intracellular calcium release in HEK293A cells stably expressing rat mGlu 5 (HEK293A-rat-mGlu 5 -low). The structure of VU0477573 is shown in comparison with the prototypical biaryl acetylene scaffold of the mGlu 5 NAMs MPEP and MTEP (Fig.…”

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

“…After extensive SAR studies, the picolinamide 45 (VU430644, Fig. 7), which has a 3-methyl-substituted oxetane as the eastern amide group, was found to fulfill both criteria (rmGlu 5 EC 50 ¼ 9.3 nM, Glu max ¼ 45%, glutamate shift ¼ 2.8) [70]. No agonist activity was observed in the low expression cell line as well as in two native systems.…”

“…Compound 45 inhibited CYP1A2 (IC 50 ¼ 5.3 μM) but had no other CYP liability. A single high-dose administered IP was reported to reverse amphetamine-induced hyperlocomotion in rats, although no details were provided [70,71]. Preliminary stability studies in acidic media showed hydrolytic ring opening of the oxetane ring which might complicate oral dosing [71].…”