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Identification of a novel dopaminergic agonist that selectively activates the D3 dopamine receptor
Author(s) -
Moritz Amy E.,
Free R. Benjamin,
Conroy Jennie,
Doyle Trevor,
Southall Noel,
Ferrer Marc,
Donthamsetti Prashant,
Javitch Jonathan A.,
Sibley David R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.655.6
Subject(s) - agonist , pharmacology , g protein coupled receptor , dopaminergic , dopamine , chemistry , drug discovery , antagonist , receptor , medicine , biochemistry
Dopamine receptors (DARs) are involved in the development and/or treatment of many neuropsychiatric disorders, with specific receptor subtypes playing distinct roles. D 2 DAR antagonism is thought to be responsible for the efficacy of antipsychotics, while D 3 DAR agonists may be useful as neuroprotective and neurorestorative antiparkinsonian medications. Many antipsychotic drugs belong to the class of 1,4‐disubstituted aromatic piperazines and piperidines (1,4‐DAPS), although many produce limiting side effects due to the high conservation of the orthosteric binding site among DAR subtypes and other related GPCRs. In order to identify novel small‐molecule ligands of DARs with the potential to be highly selective and therefore better drug candidates, our lab has employed a high throughput screening (HTS) approach. Through the NIH Molecular Libraries Program, a novel 1,4 DAP, Compound 3843, was originally identified as a D 2 antagonist in a D 2 ‐G qi5 calcium HTS of a 370,000+ small molecule library. Counter‐screening assays of beta‐arrestin recruitment revealed that this compound selectively activates the D 3 DAR and acts as an antagonist at the D 2 DAR. Compound 3843 also functions as a D 3 DAR agonist in a Go BRET activation assay. We ultimately hope Compound 3843, or its analogs, will be a useful in vitro or in vivo pharmacological tool.