Natural Product-Inspired Dopamine Receptor Ligands.

Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson's disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise.

Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity.

To illuminate the tolerance of fluoroalkoxylated groups at the C-3 and C-9 positions of tetrahydroprotoberberines (THPBs) on D1R activity, C-3 and C-9 fluoroalkoxylated analogues of (S)-12-bromostepholidine were prepared and evaluated. All compounds examined were D1R antagonists as measured by a cAMP assay. Our structure-activity studies herein indicate that the C-3 position tolerates a 1,1-difluoroethoxy substituent for D1R antagonist activity.

Structure-Activity Relationship Studies on 6-Chloro-1-phenylbenzazepines Leads to the Identification of a New Dopamine D1 Receptor Antagonist.

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, -3, C-3' and C-4' positions.

Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation.

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds and , with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling.

End-to-end sequence-structure-function meta-learning predicts genome-wide chemical-protein interactions for dark proteins.

Systematically discovering protein-ligand interactions across the entire human and pathogen genomes is critical in chemical genomics, protein function prediction, drug discovery, and many other areas. However, more than 90% of gene families remain "dark"-i.e.