(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu(5): Discovery of a new tool compound with activity in the OSS mouse model of addiction

Abstract

Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (Group I: mGlu(1) and mGlu(5); Group II: mGlu(2) and mGlu(3); Group III: mGlu(4), mGlu(6), mGlu(7), and mGlu(8)). Non-competitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu(5) offer potential therapeutic applications in diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of SAR in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu(5) antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu(5) NAM in this novel assay.

Figure 1

3-Cyano-5-fluorophenyl ring containing noncompetitive antagonists of mGlu₅.

Scheme 1

(i) Pd(^tBu₃)₂, 1 M Cs₂CO₃/THF (1:1), μw, 150 °C, 10 min. (ii) Pd(PPh₃)₄, 1 M Cs₂CO₃/THF (1:1), μw, 120 °C, 20 min. (iii) PdCl₂(dppf), 1 M Na₂CO₃/DMF (1:3), μw, 140 °C, 20 min.

Figure 2

Radioligand binding and blockade of glutamate response in rat cortical astrocytes. (A) Compound 18 potently inhibits binding of [³H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine. (B) 10 μM of compound 18 produces a near complete blockade of the response to glutamate in rat cortical astrocytes.

Figure 3

Pharmacokinetics of 18 following intraperitoneal dosing in mice demonstrated good exposure in the brain out to 1 h.

Figure 4

Inhibition of marble burying by compound 18 in mice.

Figure 5

Dose dependent reduction of progressive ratio responding for OSS stimuli, but not for food, by compound 18 in mice. OSS, n = 8; food, n = 6; *p < 0.05; ***p < 0.001.

Figure 6

Dose dependent reduction of progressive ratio responding for OSS stimuli, but not for food, by MTEP in mice. OSS, n = 8; Food, n = 8; *p < 0.05.