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

Abstract

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 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.

Natural Product-Inspired Dopamine Receptor Ligands

“…Our initial efforts were focused on SAR studies with l -SPD as a lead molecule. So far, our attempts to identify new selective D 1 R partial agonist/D 3 R antagonist dual-acting ligands from THPBs have not been successful, although we have identified several dopamine receptor subtype-specific ligands (e.g., 77 – 80 ). − , Our structure–affinity relationship studies on l -SPD revealed that bromination at the C-12 position improved D 1 R affinity but generally diminished D 3 R affinity. Homologation at the C-9 position improved D 1 R selectivity versus D 2 R and D 3 R (often lacking affinity at D 2 R), whereas alkylation of the C-10 phenolic group with up to 6 carbon atoms in length was tolerated for D 1 R affinity.…”

“…In efforts to improve the efficacy and safety of THPBs, our group is actively working on fine tuning the polypharmacology of THPBs as selective D 1 R partial agonist/D 3 R antagonist dual-acting ligands. − This targeting strategy is based on the observation that coadministration of a D 1 R partial agonist (SKF 77434) and a D 3 R antagonist (NGB 2904) produced robust decreases in cocaine seeking and reward in rats. This indicates a synergistic effect between D 1 R agonism and D 3 R antagonism .…”

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

“…Disturbances in dopaminergic neurotransmission have significant implications for neurological disorders such as Parkinson’s disease, schizophrenia and psychostimulant disorders. There is a current interest in the deployment of selective D1R full agonists/partial agonists to treat these conditions [ 16 , 17 , 18 , 19 , 20 , 21 ]. Classical D1R agonists contain a catechol motif that is associated with suboptimal pharmacokinetic properties, including diminished blood-brain barrier penetration and poor oral bioavailability.…”

“…Molecules 2023, 28, 6010 2 of 17 disorders. There is a current interest in the deployment of selective D1R full agonists/partial agonists to treat these conditions [16][17][18][19][20][21]. Classical D1R agonists contain a catechol motif that is associated with suboptimal pharmacokinetic properties, including diminished bloodbrain barrier penetration and poor oral bioavailability.…”