Stereoisomeric probes for the D1 dopamine receptor: synthesis and characterization of R-(+) and S-(-) enantiomers of 3-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its 6-bromo analogue.
Substituted 1-phenyl-3-benzazepines (e.g., SKF 38393 and fenoldopam) exhibit stereoselectivity in moderately high-affinity binding to and partial agonist activation of D1 dopamine receptors. The 3-allyl (APB) and the 3-allyl-6-chloro (6-Cl-APB) analogues of SKF 38393 are reported to have higher affinity and selectivity for the D1 DA receptor and higher in vivo central neuropharmacologic activity than SKF 38393. We recently reported the corresponding 3-allyl-6-bromo analogue (6-Br-APB) also to be a high-affinity D1 agonist. We now describe the synthesis and characterization of the R-(+) and S-(-) enantiomers of both APB and 6-Br-APB and their comparison with corresponding enantiomers of SKF 38393 with respect to D1 receptor binding affinity and D1 and D2 selectivity. The R-(+) enantiomers of both novel substituted 1-phenyl-3-benzazepines bound to the D1 receptor sites in rat forebrain tissue with much higher affinity and selectivity than their S-(-) antipodes. R-(+)-3-Allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine [(R)-(+)-6-Br-APB, 18] exhibits the highest affinity of the reported 1-phenyl-3-benzazepine D1 agonists.
Neumeyer
J L
JL
Research Biochemicals Inc., Natick, Massachusetts 01760.
Kula
N S
NS
Baldessarini
R J
RJ
Baindur
N
N
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001552:Benzazepines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C074280:3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C067114:SK&F 77434