mGluR5 Negative Allosteric Modulators Overview: A Medicinal Chemistry Approach towards a Series of Novel Therapeutic Agents.

18:32 EDT 30th August 2015 | BioPortfolio

Summary of "mGluR5 Negative Allosteric Modulators Overview: A Medicinal Chemistry Approach towards a Series of Novel Therapeutic Agents."

Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.


Addex Pharma SA, Core Chemistry Department, Chemin des Aulx 12, 1228 Plan-les-Ouates Geneva, Switzerland.

Journal Details

This article was published in the following journal.

Name: Current topics in medicinal chemistry
ISSN: 1873-4294


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Medical and Biotech [MESH] Definitions

Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.

Organic chemistry methodology that mimics the modular nature of various biosynthetic processes. It uses highly reliable and selective reactions designed to "click" i.e., rapidly join small modular units together in high yield, without offensive byproducts. In combination with COMBINATORIAL CHEMISTRY TECHNIQUES, it is used for the synthesis of new compounds and combinatorial libraries.

Chemistry dealing with the composition and preparation of agents having PHARMACOLOGIC ACTIONS or diagnostic use.

The branch of chemistry dealing with detection (qualitative) and determination (quantitative) of substances. (Grant & Hackh's Chemical Dictionary, 5th ed)

Field of chemistry pertaining to the study of inorganic compounds or ions and their interactions with biological ligands at the molecular level.


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