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Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.

ABSTRACT: The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final probe 65 was obtained through a quantitative high-throughput screening campaign, followed by medicinal chemistry optimization, to yield a selective molecule with good in vitro physical properties, metabolic stability, and in vivo pharmacokinetics. The optimized molecule may be a useful in vivo probe for studying D2 DAR signal modulation and could also serve as a lead compound for the development of D2 DAR-selective druglike molecules for the treatment of multiple neuropsychiatric and endocrine disorders.

SUBMITTER: Xiao J

PROVIDER: S-EPMC4315423 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.

Xiao Jingbo J Free R Benjamin RB Barnaeva Elena E Conroy Jennie L JL Doyle Trevor T Miller Brittney B Bryant-Genevier Marthe M Taylor Mercedes K MK Hu Xin X Dulcey Andrés E AE Southall Noel N Ferrer Marc M Titus Steve S Zheng Wei W Sibley David R DR Marugan Juan J JJ

Journal of medicinal chemistry 20140410 8

The D2 dopamine receptor (D2 DAR) is one of the most validated drug targets for neuropsychiatric and endocrine disorders. However, clinically approved drugs targeting D2 DAR display poor selectivity between the D2 and other receptors, especially the D3 DAR. This lack of selectivity may lead to undesirable side effects. Here we describe the chemical and pharmacological characterization of a novel D2 DAR antagonist series with excellent D2 versus D1, D3, D4, and D5 receptor selectivity. The final ...[more]

PMID: 24666157

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Dataset Information

Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.

Publications

Discovery, optimization, and characterization of novel D2 dopamine receptor selective antagonists.

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