Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.

摘要: To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to suitably oriented aromatic ring (i.e., axial orientation approximately orthogonal catechol nucleus) agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) are selective for this subtype, cis- trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds 5,6-ethano-bridged derivatives of receptor agonist 1. Introduction bridge reduces conformational mobility parent molecule. Comprehensive analyses by molecular mechanical methods indicated both cis trans isomers could attain conformation places phenyl substituent orientation. X-ray analysis isomer showed disposition ring; however, NMR studies suggest is fixed isomer, but not cis. The binding affinity intrinsic activity considerably greater than those its counterpart; also demonstrated high degree selectivity subtypes. One possible explanation these results, suggested modeling studies, postulated be required putatively requisite nitrogen plane can attained only which tetrahydroazepine twist conformation. Conversely, results simply preference benzazepine having group equatorial Still another possibility sterically hindered area accessible relatively planar. However, it requires 1-phenylbenzazepine strong binding. Thus, conformationally flexible more readily achieve different conformations gain access bind with site.