Synthesis and Structure−Activity Relationships of 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine Analogues as Potent, Noncompetitive Metabotropic Glutamate Receptor Subtype 5 Antagonists; Search for Cocaine Medications

Abstract

Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.

Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats

“…These data suggest that acamprosate can antagonize metabotropic glutamate receptors as well as ionotropic glutamate receptors. Indeed, the mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine attenuates both cocaine-and cue-induced reinstatement of cocaine-seeking behavior (Backstrom and Hyytia 2006;Iso et al 2006;Lee et al 2005). However, mGlu5 antagonists also attenuate baseline cocaine self-administration patterns (Chiamulera et al 2001;Kenny et al 2003Kenny et al , 2005Tessari et al 2004), an effect that was not observed with acamprosate in the present study.…”

Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses

“…Likewise, many members of the CDPPB series can also act as allosteric potentiators of mGluR1, but none of these compounds has neutral or allosteric antagonist activity at mGluR1 . Furthermore, analysis of analogs of MPEP has yielded many allosteric antagonists and a small number of neutral ligands but no allosteric potentiators in the MPEP series (Gasparini et al, 1999;Alagille et al, 2005a,b;Rodriguez et al, 2005;Iso et al, 2006). This suggests clear differences in the structural requirements of different activities at allosteric sites on mGluRs.…”

Group I mGluRs and Long-Term Depression: Potential Roles in Addiction?

“…Most profoundly, mGluR5-null mutant mice are insensitive to the locomotor-stimulating and rewarding properties of cocaine [19]. Consistent with this phenotype, the mGluR5 specific antagonists, MPEP and MTEP, attenuate cocaine-mediated behaviors [61], including cue-induced relapse to cocaine seeking [5,19,48]. These antagonists also disrupt reinforcing properties of alcohol [76].…”