Effects of LY354740, a Novel Glutamatergic Metabotropic Agonist, on Nonhuman Primate Hypothalamic-Pituitary-Adrenal Axis and Noradrenergic Function

  title={Effects of LY354740, a Novel Glutamatergic Metabotropic Agonist, on Nonhuman Primate Hypothalamic-Pituitary-Adrenal Axis and Noradrenergic Function},
  author={Jeremy D Coplan and Sanjay J. Mathew and E. Smith and Ronald C. Trost and Bruce A. Scharf and J M Martinez and Jack M. Gorman and James A. Monn and Darryle D. Schoepp and Leonard A. Rosenblum},
  journal={CNS Spectrums},
  pages={607 - 617}
Abstract The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach… 
LY354740, an mGlu2/3 Receptor Agonist as a Novel Approach to Treat Anxiety/Stress
Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO 2 challenge), and data indicate mGlu2/3 receptor agonists such as LY 354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.
New perspectives in glutamate and anxiety
Molecular targets in the treatment of anxiety
New molecular targets for antianxiety interventions.
  • J. Gorman
  • Psychology, Biology
    The Journal of clinical psychiatry
  • 2003
The gamma-aminobutyric acid (GABA) system has long been targeted in anxiety interventions via benzodiazepine-GABA receptor antagonists and agents that target specific subunits of the GABA-A receptor and that manipulate GABA levels are developed.
Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists
This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials, and describes the potential value of mGLUR2 and mGlamR5 agonists and positive allosteric modulators for the treatment of schizophrenia.
Developmental expression of mGlu2 and mGlu3 in the mouse brain.


Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors.
A functional role for group II mGluRs in fear/anxiety responses in animals is indicated and compounds in this class may be beneficial in the treatment of anxiety-related disorders in humans without the side effects seen with currently prescribed medications.
Potent, stereoselective, and brain region selective modulation of second messengers in the rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist
Data indicate that LY354740 is a highly potent, efficacious, and selective Group II mGlu receptor (mGlu 2/3) agonist in the rat brain.
Metabotropic glutamate receptor in vasopressin, CRF and VIP hypothalamic neurones
The results support the view that the excitatory transmitter glutamate may directly influence AVP, CRF and VIP neurones of the three hypothalamic cell groups.
Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders.
Grown nonhuman primates who were exposed as infants to adverse early rearing conditions were studied to determine if long-term alterations of CRF neuronal systems had occurred following the early stressor.
Novel functions for subtypes of metabotropic glutamate receptors
  • D. Schoepp
  • Biology, Chemistry
    Neurochemistry International
  • 1994