C-Ring expanded analogs of doxanthrine: Conformation plays a critical role

Abstract

To assess the importance of conformation and placement of the ß-substituent of agonist ligands targeted to the D1 dopamine receptor, (±)-trans-6,6a,7,8,13,13a-hexahydrobenzo[e]chromeno [3,4-b]azepine-2,3- diol 5 and (±)-trans-6,6a,7,8,9,13b-hexahydrobenzo[d]chromeno[3,4-b] azepine-2,3-diol 6 were synthesized as ring-expanded analogues of the high affinity D1 dopamine receptor selective agonist doxanthrine, using a novel tetrahydrobenzazepine ring-forming strategy. Compounds 5 and 6 had only micromolar affinity at the D1 receptor. Molecular modeling show deviations in the orientation of the accessory phenyl ring between 4 and its ring expanded analogs 5 and 6. Furthermore, the additional methylene group in the azepine ring may cause an unfavorable steric intrusion into the receptor binding process. These conformational differences suggest that the placement of the accessory phenyl ring must be well defined. © ARKAT USA, Inc.