L-Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), which acts through the ligand-gated ionotropic glutamate receptor or through the G-protein coupled receptors (GPCR) called metabotropic glutamate receptors (mGluR). The mGluR5 belongs to the Group I subclass and is coupled to the phosphoinositide/Ca+2 pathway, which mainly mediates the excitatory effects of glutamate. Recently, investigation into the role of mGluR5 in drug abuse has led to speculation that this may be a new target for medication development. For example, studies using either an mGluR5 antagonist or mGluR5 knockout mice showed reduced locomotor stimulant effects induced by cocaine. Moreover, evidence that mGluR5 is involved in the rewarding effects of morphine, nicotine and ethanol has also been reported. Thus development of selective mGluR5 antagonists may provide a novel non-dopaminergic strategy toward the discovery of drug abuse medications. Additionally the mGluR5 has recently been implicated in anxiety and depression thus these antagonists might provide new therapeutic agents toward the treatment of these CNS disorders. In order to further explore structure-activity relationships (SAR) at mGluR5, the design and synthesis of a series of diaryl amides was initiated based on a putative ligand binding site at the transmembrane domain region of an mGluR5 molecular model, based on the bovine rhodopsin crystal structure. In vitro binding and functional evaluation at mGluR5 resulted in the discovery of several novel and high affinity mGluR5 antagonists that are currently be evaluated in animal models of drug abuse.
| Kulkarni, Santosh S; Newman, Amy Hauck (2007) Discovery of heterobicyclic templates for novel metabotropic glutamate receptor subtype 5 antagonists. Bioorg Med Chem Lett 17:2987-91 |
| Kulkarni, Santosh S; Newman, Amy Hauck (2007) Design and synthesis of novel heterobiaryl amides as metabotropic glutamate receptor subtype 5 antagonists. Bioorg Med Chem Lett 17:2074-9 |
| Kulkarni, Santosh S; Nightingale, Barbara; Dersch, Christina M et al. (2006) Design and synthesis of noncompetitive metabotropic glutamate receptor subtype 5 antagonists. Bioorg Med Chem Lett 16:3371-5 |
