Understanding GPCR signaling in the brain- the path to CNS drug discovery

2017 ◽  
Vol 32 ◽  
pp. v-vii
Author(s):  
David Chatenet ◽  
Terence E. Hébert
Keyword(s):  
Drug Discovery ◽  
Gpcr Signaling ◽  
The Brain

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals Latrophilin GPCR Signaling Mediates Synapse Formation

2021 ◽  
Author(s):  
Richard Sando ◽  
Thomas C. Südhof
Keyword(s):  
Synapse Formation ◽  
Neural Circuit ◽  
Gpcr Signaling ◽  
Synapse Loss ◽  
Ca1 Region ◽  
In Trans ◽  
Synaptic Complexes ◽  
Camp Levels ◽  
The Brain

ABSTRACTNeural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

From the Explored to the Unexplored: Computer-Tailored Drug Design Attempts in the Discovery of Selective Caspase Inhibitors

2019 ◽  
Vol 22 (7) ◽  
pp. 432-444
Author(s):  
Ransford O. Kumi ◽  
Abdul R. Issahaku ◽  
Opeyemi S. Soremekun ◽  
Clement Agoni ◽  
Fisayo A. Olotu ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Therapeutic Effects ◽  
Computer Aided Drug Design ◽  
Neurologic Diseases ◽  
Caspase Inhibitors ◽  
Caspase Inhibition ◽  
Selective Targeting ◽  
Computer Aided ◽  
The Brain

The pathophysiological roles of caspases have made them attractive targets in the treatment and amelioration of neurologic diseases. In normal conditions, the expression of caspases is regulated in the brain, while at the onset of neurodegeneration, such as in Alzheimer’s disease, they are typically overexpressed. Till date, several therapeutic efforts that include the use of small endogenous binders have been put forward to curtail dysfunctionalities that drive aberrant death in neuronal cells. Caspases are highly homologous, both in structure and in sequence, which leaves us with the question: is it possible to specifically and individually target caspases, while multiple therapeutic attempts to achieve selective targeting have failed! Based on antecedent events, the use of Computer-Aided Drug Design (CADD) methods has significantly contributed to the design of small molecule inhibitors, especially with selective target ability and reduced off-target therapeutic effects. Interestingly, we found out that there still exists an enormous room for the integration of structure/ligand-based drug design techniques towards the development of highly specific reversible and irreversible caspase inhibitors. Therefore, in this review, we highlight drug discovery approaches that have been directed towards caspase inhibition in addition to an insightful focus on applicable CADD techniques for achieving selective targeting in caspase research.

In-Depth GPCR Signaling Characterization for Improved Drug Discovery

2020 ◽  
Vol 40 (8) ◽  
pp. 60-62
Author(s):  
Arturo Mancini ◽  
Laurent Sabbagh
Keyword(s):  
Drug Discovery ◽  
Gpcr Signaling

Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery

2018 ◽  
Vol 25 (29) ◽  
pp. 3455-3481 ◽  
Author(s):  
Agnieszka Zagorska ◽  
Anna Partyka ◽  
Adam Bucki ◽  
Alicja Gawalskax ◽  
Anna Czopek ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Neurodegenerative Diseases ◽  
Medicinal Chemistry ◽  
Point Of View ◽  
Medium Spiny Neurons ◽  
Lead Discovery ◽  
Spiny Neurons ◽  
Wide Range ◽  
The Brain

Background: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. Objective: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson’s, Huntington’s, and Alzheimer’s diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.

scholarly journals Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood–Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 595 ◽  
Author(s):  
Cui ◽  
Lotz ◽  
Rapp ◽  
Klinder ◽  
Himstedt ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Partition Coefficient ◽  
Blood Brain Barrier ◽  
New Method ◽  
Brain Barrier ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
The Brain

Movement of xenobiotic substances across the blood–brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new central nervous system (CNS) drugs. Drug efflux at the BBB is described by the partition coefficient of unbound drug between brain and plasma (Kp,uu,brain) which is typically obtained from in vivo and often additionally in vitro measurements. Here, we describe a new method for the rapid estimation of the in vivo drug efflux at the BBB of rats: the measurement of the partition coefficient of a drug between brain and skeletal muscle (Kp,brain/muscle). Assuming a closely similar distribution of drugs into the brain and muscle and that the efflux transporters are only expressed in the brain, Kp,brain/muscle, similar to Kp,uu,brain, reflects the efflux at the BBB. The new method requires a single in vivo experiment. For 64 compounds from different research programs, we show the comparability to other approaches used to obtain Kp,uu,brain. P-gp- and BCRP-overexpressing cell systems are valuable in vitro tools for prescreening. Drug efflux at the BBB can be most accurately predicted based on a simple algorithm incorporating data from both in vitro assays. In conclusion, the combined use of our new in vivo method and the in vitro tools allows an efficient screening method in drug discovery with respect to efflux at the BBB.

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