qHTS of D3 Dopamine Receptor Potentiators: qHTS
D3 DARs represent a very important target for the treatment of several neuropsychiatric disorders. Indeed, one of the most promising therapeutic applications for the D3 DAR is in the area of addiction and related disorders. Several lines of evidence suggest that partial agonists or antagonists of the D3 DAR may be therapeutic for drug abuse and relapse. Accumulating evidence suggests that more ..
BioActive Compounds: 2381
D3 DARs represent a very important target for the treatment of several neuropsychiatric disorders. Indeed, one of the most promising therapeutic applications for the D3 DAR is in the area of addiction and related disorders. Several lines of evidence suggest that partial agonists or antagonists of the D3 DAR may be therapeutic for drug abuse and relapse. Accumulating evidence suggests that reducing D3 DAR activity may regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving and relapse or reinstatement of drug taking. These findings have been observed with a number of addictive substances including cocaine, amphetamine, nicotine, and alcohol. It is particularly interesting that partial agonists are effective in these preclinical models, suggesting that only partial blockade of the D3 DAR is needed and may, in fact, prove to be more beneficial than full blockade. Antagonism of the D3 DAR may also be therapeutic in the treatment of schizophrenia or psychosis. Notably, while all antipsychotic drugs block the D2 DAR, they also block the D3 DAR to various degrees. Since the D3 DAR is expressed in areas of the CNS associated with the control of mood and emotion, it has been hypothesized that selective antagonism of the D3 DAR may be effective in treating psychosis without inducing the motor side effects typically seen with D2 DAR antagonists. Interestingly, D3 DAR antagonism has also been suggested to be highly beneficial in the treatment of certain motor/movement disorders such as L-DOPA-induced dyskinesias, which typically arise during late-stage Parkinson's disease treatment.
The goal of this project is to use high throughput screening approaches to identify and develop novel, highly selective small molecule allosteric modulators of the D3 DAR for use as in vitro and in vivo pharmacological tools and in proof-of-concept experiments in animal models of neuropsychiatric disease. This part of the project aims to discover novel potentiators.
NIH Chemical Genomics Center [NCGC]
NIH Molecular Libraries Probe Centers Network [MLPCN]
MLPCN Grant: MH094203
Assay Submitter (PI): David Sibley, NINDS
Freshly passaged cells are plated in 1536 well white, solid bottom plates at a density of 1500 cells/well in 3microl of complete media. After an overnight incubation at 37 degrees C in 5% CO2, cells are loaded with 23nl of test compound from the compound library (as well as dopamine controls) using a 1536 pintool. Cells are then loaded with microl of an EC20 concentration of DA and incubated at 37 degrees C for 90 minutes. Two microliters of DiscoveRx reagent is then added to all cells, and they are incubated for an additional 30 - 60 minutes at room temperature. Following incubation, luminescence is measured on a ViewLux CCD-based luminometer reader using a 20 sec exposure time.
Compounds whose "max activity" is <= 30% are considered "active" and assigned a score of 90; for compounds with a "max activity" < 30% are considered "inactive" and are assigned a score of 10.
** Test Concentration.
Data Table (Concise)