Dopamine/Serotonin Receptor Ligands. 12:  SAR Studies on Hexahydro-dibenz[d,g]azecines Lead to 4-Chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the First Picomolar D₅-Selective Dopamine-Receptor Antagonist

Abstract

Hydroxylated, methoxylated, and/or chlorinated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines were generally synthesized out of substituted 2-phenylethylamines and isochromanones by Bischler-Napieralski cyclization of the resulting benzamides to dibenzoquinolizines and the quaternization and cleavage of the central C-N bond under Birch conditions. Chlorination of 2-phenylethylamines was useful for the site direction of cyclization, but chlorine atoms were removed under Birch conditions so that chlorination had to be repeated to get the respective chlorinated dibenz[d,g]azecines. The target compounds were tested for their affinity at the different human-cloned dopamine-receptor subtypes (D1 family, D2 family). Generally, hydroxylation and chlorination of the dibenz-azecines increased affinities significantly. 1-Chloro-2-hydroxy-hexahydro-dibenz[d,g]azecine was a subnanomolar antagonist at both subtype families. 4-Chloro-3-hydroxy-7-methyl-5,6,7,8,9,14-hexahydro-dibenz[d,g]azecine was identified as the most potent and selective dopamine D5 receptor ligand described to date with Ki(D1)=0.83, Ki(D2L)=4.0, Ki(D3)=24.6, Ki(D4)=5.2 nM, and Ki(D5)=57 pM (radioligand binding experiments), respectively.

Enzymatic Baeyer–Villiger Oxidation of Benzo‐Fused Ketones: Formation of Regiocomplementary Lactones

“…1‐Isochromanone ( 4c ) was prepared according to the literature,14 by oxidizing isochromane with NaClO 2 and N ‐hydroxyphthalimide in CH 3 CN/H 2 O (66 % yield). Compounds 1b ,15a 2b ,15b 3b ,15c 4b ,15d 5b ,8 7b ,15e 9b ,15f 10b ,15g 4c ,14 6c 15h and 9c 15i exhibit physical and spectral properties in accord with those reported previously.…”

The cooperative roles of the dopamine receptors, D 1 R and D 5 R, on the regulation of renal sodium transport

“…A new D 5 R antagonist (LE-PM436) 28 was utilized to distinguish signaling of D 5 Rs from D 1 Rs. To validate its selectivity, we used HEK293 cells that were stably transfected with either D 1 R or D 5 R cDNA and expressed these receptors at normal physiological concentrations, measured at 3 pmoles/mg membrane protein.…”

A Novel Non‐phenolic Dibenzazecine Derivative with Nanomolar Affinities for Dopamine Receptors

“…The newly synthesized derivative 3 showed high affinities similar to the lead LE404, displaying nanomolar affinities for all dopamine receptor subtypes. Its dibrominated derivative 4, though exhibiting almost a fivefold decrease in affinities, still displayed nanomolar ones for all dopamine receptors, except for D 4 . In a functional Ca 2 þ assay, both compounds 3 and 4 were found to possess antagonistic properties towards the dopamine receptors.…”

“…Dibenz [d,g]azecines are a novel class of dopamine receptor antagonists, which are distinguished by their new chemical structure, as well as their high affinities for dopamine receptors, predominantly for the D 1 family [3] [4]. SAR Studies on this new class of compounds revealed that derivatives that encompass a dibenz[d,g]azecine moiety as the backbone structure and bear a OH substituent at C(3) (e.g., compound 1; LE404; Fig.…”

“…), display the highest affinities, specifically for human D 1 and D 5 receptors [3 -5]. Changing the position of the OH group or replacing it by a MeO group both led to decreased affinities [4]. Surprisingly, a 2,3-dihydroxy substitution pattern (compound 2; LE403; Fig.…”