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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. firstname.lastname@example.org.
This article was published in the following journal.
Name: Current topics in medicinal chemistry
5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569, 1) is a prototypical allosteric modulator for the cannabinoid CB1 receptor. Based on this indole-2-carboxamide scaff...
Allosteric ligands modulate the activity of receptor targets by binding to sites that are distinct from the orthosteric (native agonist) binding site. Allosteric modulators have potential therapeutic ...
The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capabl...
The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labelin...
Allosteric modulation is the regulation of a protein by binding of an effector molecule at the proteins allosteric site (a site other than that of the endogenous ligand). Allosteric modulators, by vir...
The study is carried out in order to determine the relationship between AZD2066 exposure and mGluR5 receptor occupancy in the brain and to demonstrate that AZD2066 can displace [11C]AZ1271...
The purpose of this study is to determine if AZD2516 binds to mGluR5 receptors in the brain. This will then help to make accurate predictions of efficacy and dosing in the future developme...
Objective: Cocaine addiction continues to be an important public health problem with over 1.7 million users in the US alone. Cocaine addiction is characterized by compulsive drug use desp...
Background: - A small brain protein called the metabotropic glutamate receptor subtype 5 (mGluR5) may affect several brain diseases such as autism and depression. Researchers will use 2 ...
For the primary goals, we hypothesize that 1) the oral tobacco product will be more efficacious than the medicinal nicotine product; 2) among non-abstainers, the oral tobacco product will ...
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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.
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase 'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...
Neurology - Central Nervous System (CNS)
Alzheimer's Disease Anesthesia Anxiety Disorders Autism Bipolar Disorders Dementia Epilepsy Multiple Sclerosis (MS) Neurology Pain Parkinson's Disease Sleep Disorders Neurology is the branch of me...