Identification of allosteric modulators of the D2 dopamine receptor (662.6)

The D2 dopamine receptor (DAR) is central in the etiology and/or therapy of numerous neuropsychiatric disorders. Unfortunately, truly specific drugs for this receptor have been difficult to obtain, primarily due to high conservation of the orthosteric binding site. We have employed a high throughput-screening approach using the 380,000 small molecule NIH MLPCN library to identify novel allosteric modulators of the D2 DAR. The primary screen was conducted using a cell line expressing an inducible D2 DAR coupled to a chimeric Gqi5 protein, thus linking receptor activation to Ca2+ mobilization. Hits were subjected to an extensive triage strategy to characterize DAR activity and selectivity. On the basis of these analyses, 745 agonist and 499 antagonist compounds were selected and evaluated using radioligand binding competition assays to identify the nature of their receptor interactions (orthosteric or allosteric). Compounds that are ineffective in competing for binding likely exert their functional activity...