Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.
To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds are 5,6-ethano-bridged derivatives of the D-1 selective dopamine receptor agonist 1. Introduction of the bridge reduces the conformational mobility of the parent molecule. Comprehensive conformational analyses by molecular mechanical methods indicated that both the cis and trans isomers could attain a conformation that places the phenyl substituent in an axial orientation. X-ray analysis of the trans isomer showed an axial disposition of the phenyl ring; however, NMR studies suggest that this conformation is fixed in the trans isomer, but not in the cis. The dopamine receptor binding affinity and intrinsic activity of the cis isomer were considerably greater than those of its trans counterpart; the cis isomer also demonstrated a high degree of selectivity for the D-1 subtypes. One possible explanation of these results, suggested by the molecular modeling studies, is that both the axial orientation of the phenyl postulated to be required for binding to the receptor and a putatively requisite location of the nitrogen in approximately the plane of the catechol ring can be attained only by the cis isomer in which the tetrahydroazepine ring is in a twist conformation. Conversely, these results might simply suggest a preference of the D-1 receptors for benzazepine agonists having the phenyl group in an equatorial orientation. Still another possibility is that the D-1 receptor binding site is in a sterically hindered area accessible only to compounds that are relatively planar. However, it requires an axial 1-phenylbenzazepine for strong binding. Thus, a conformationally flexible cis isomer could more readily achieve the different conformations required to both gain access to and bind with the D-1 site.
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018818:Fenoldopam; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1
D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D018818:Fenoldopam; D004298:Dopamine