Ta. Knoerzer et al., SYNTHESIS AND BIOLOGICAL EVALUATION OF A SERIES OF SUBSTITUTED BENZO[A]PHENANTHRIDINES AS AGONISTS AT D-1 AND D-2 DOPAMINE-RECEPTORS, Journal of medicinal chemistry, 38(16), 1995, pp. 3062-3070
Dihydrexidine [4; rans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo [
a]phenanthridine (DHX)], the first high-affinity full D-1 agonist, als
o is known to have significant D-2 activity. The present work reports
the synthesis and pharmacological activity of a series of analogs subs
tituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). oxy-
5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine (5) was a high-affinity
D-1 agonist, having approximately 4-fold greater D-1 vs D-2 selectivi
ty than DHX itself. All of the analogs containing a methyl or ethyl (b
ut not a phenyl) substituent at the 2-, 3-, or 4-position had a pharma
cological profile similar to that of the lead compound DHX (4). Each a
nalog was found to be a high-affinity full agonist with moderate selec
tivity for the D-1 receptor, It is apparent from these results that th
e D-1 receptor can tolerate small substituents at the 2-, 3-, and 4-po
sitions of the pendent phenyl ring. On the basis of earlier studies sh
owing that N-alkylation increases D-2 selectivity, the 3-methyl N-n-pr
opyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. Whi
le these analogs exhibited much higher affinity for the D-2 receptor,
surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for bo
th the D-1 and D-2 receptors. It was subsequently established that thi
s compound is a selective D-3 ligand (110-fold selectivity for the D-3
over D-2 receptor). The results from these studies demonstrate that s
everal of the hexahydrobenzo[a]phenanthridine derivatives are agonists
with high intrinsic activity that may serve as powerful tools to expl
ore the structural features that determine affinity and selectivity (r
elative to the D-2 receptor) of drugs for D-1 receptors.