Analogues of doxanthrine reveal differences between the dopamine D1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

Abstract

Efforts to develop selective agonists for dopamine D1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric β-phenyldopamine-type full agonist ligands that display selectivity and potency at D1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D1- and D2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D1-like receptor binding, suggesting important differences between the interactions of these ligands with the D1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor.

Characterization of Gαsand Gαolfactivation by catechol and non-catechol dopamine D1 receptor agonists

“…It has been reported that the restricted conformation of the β-phenyl-dopamine pharmacophore renders the selectivity and full agonism at D1R of catechol D1R agonists. 36 Here, we expanded on this finding and revealed a differential activation profile of DHX, m-DHX, and DOX at two homologous G protein subtypes , Gαs and Gαolf. While these compounds exerted full agonism at Gαs, they behaved as partial agonists at Gαolf.…”

“…In this study, we investigated a series of D1R agonists with diverse structures from both catechol (dihydrexidine (DHX), methyl-dihydrexidine (m-DHX), doxanthrine (DOX)) 36 and non-catechol (tavapadon (TAV), PF-8294, PF-6142) 19 classes. Unlike the control compounds (i.e., DA, SKF38393, SKF81297), there was a discernible difference in the efficacy of these agonists, relative to DA, at Gα s and Gα olf .…”

Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary

“…Arylation of the N -methoxyamide derived from alanine with a variety of heterocyclic aryl iodides on gram scales to make various unnatural amino acids was also demonstrated. These unnatural amino acid intermediates were further transformed to drug molecules such as a human kynurenine aminotransferase (KAT) II inhibitor 11 and Doxanthrine, 12 as well as chiral hydroxamic acid ligands 13 and a variety of new chiral pyridine-2,6-bis(oxazolines) (PyBOX) ligands 14 (Figure 2). …”