Ring Expansions of Tetrahydroprotoberberines and Related Dibenzo[c,g]azecines Modulate the Dopamine Receptor Subtype Affinity and Selectivity

Abstract

The affinities of tetrahydroprotoberberines for dopamine receptors dramatically decrease after cleaving the central C-N bond to the analogous ten-membered dibenzo[c,g]azecines [1]. In the present work, we also synthesized eleven-membered homologues of these heterocycles and measured the affinities of the resulting dibenzazaundecenes and their underlying homoberberines for human dopamine receptors as well as the cytotoxic effects of all target compounds on human glia cells. The tetracyclic iso-C-homoberberine-derivatives revealed to be D(4)-selective antagonists, while all other active compounds showed a significant D(1)/D(5) selectivity. Distances in energy-minimized conformations were measured in order to explain our findings.

Update 1 of: Recent Progress in Development of Dopamine Receptor Subtype-Selective Agents: Potential Therapeutics for Neurological and Psychiatric Disorders

“…The corresponding carbocyclic analog 92 displayed 4- (D 1 ) and 30-fold (D 5 ) less affinity than 91 . Further expansion of the central N -heterocycle was also conducted similar to the case of the benzindoloazecine series, leading to analogs 93 – 98 (Figure ). − Enlarging the dibenzazecines to the corresponding dibenzazacycloundecenes 92 and 93 and dibenzazacyclododecene 94 generally yielded lower but still substantial affinity for D 1 and D 5 receptors (3.2–95 nM; Table ). The position of the nitrogen in relation to the substituted benzene ring appeared to be crucial.…”

“…They had D 4 K i values of 224 and 282 nM, and >10 μM at D 2 and D 3 receptors, respectively. 108 3.4. 44) was a reported potential D 4 -receptor ligand.…”

“…As analogs of D 1 –D 2 agonist tetrahydroprotoberberines, the homo- C -congeners 519 and 520 showed moderate affinity but substantial selectivity for the D 4 receptor. They had D 4 K i values of 224 and 282 nM, and >10 μM at D 2 and D 3 receptors, respectively …”