Article

Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 1: Identification and synthesis of phenyl-tetrazolyl acetophenones.

Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 12/2004; 14(21):5329-32. DOI: 10.1016/j.bmcl.2004.08.020
Source: PubMed

ABSTRACT We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation).

0 Followers
 · 
73 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology. Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain. High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia. Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor. A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists. Areas covered: This review covers the patent applications which were published between April 2009 and December 2012 on PAMs of the mGlu2, and it is a continuation of an earlier review published in this journal. Expert opinion: Advances in medicinal chemistry and pharmacology have set the stage in the field of mGlu2 receptor PAMs. Compounds currently advancing in clinical trials will soon establish the therapeutic potential of this allosteric approach.
    Expert Opinion on Therapeutic Patents 03/2013; DOI:10.1517/13543776.2013.777043 · 3.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Group II metabotropic glutamate (mGlu) receptors consist of the metabotropic glutamate 2 (mGlu(2)) and metabotropic glutamate 3 (mGlu(3)) receptor subtypes which modulate glutamate transmission by second messenger activation to negatively regulate the activity of adenylyl cyclase. Excessive accumulation of glutamate in the perisynaptic extracellular region triggers mGlu(2) and mGlu(3) receptors to inhibit further release of glutamate. There is growing evidence that the modulation of glutamatergic neurotransmission by small molecule modulators of Group II mGlu receptors has significant potential for the treatment of several neuropsychiatric and neurodegenerative diseases. This review provides an overview of recent progress on the synthesis and pharmacological characterization of positive and negative allosteric modulators of the Group II mGlu receptors.
    ACS Chemical Neuroscience 08/2011; 2(8):382-93. DOI:10.1021/cn200008d · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: As part of our ongoing small-molecule metabotropic glutamate (mGlu) receptor positive allosteric modulator (PAM) research, we performed structure-activity relationship (SAR) studies around a series of Group II mGlu PAMs. Initial analogues exhibited weak activity as mGlu2 receptor PAMs and no activity at mGlu3. Compound optimization led to the identification of potent mGlu2/3 selective PAMs with no in vitro activity at mGlu1,4-8 or forty-five other CNS receptors. In vitro pharmacological characterization of representative compound 44 indicated agonist-PAM activity toward mGlu2 and PAM activity at mGlu3. The most potent mGlu2/3 PAMs were characterized in assays predictive of ADME/T and pharmacokinetic (PK) properties, allowing the discovery of systemically active mGlu2/3 PAMs. Based on its overall profile, compound 74 was selected for behavioral studies and was shown to dose-dependently decrease cocaine self-administration in rats after intraperitoneal administration. These mGlu2/3 receptor PAMs have significant potential as small molecule tools for investigating Group II mGlu pharmacology.
    Journal of Medicinal Chemistry 04/2014; 57(10). DOI:10.1021/jm5000563 · 5.48 Impact Factor

Similar Publications