Wk. Brewster et al., EVALUATION OF CIS AND TRANS-9 AND XY-5,6,6A,7,8,12B-HEXAHYDROBENZO[A]PHENANTHRIDINES AS STRUCTURALLY RIGID, SELECTIVE D-1 DOPAMINE-RECEPTORLIGANDS, Journal of medicinal chemistry, 38(2), 1995, pp. 318-327
The present study reports the investigation of the D-1 structure-relat
ionships of certain cis- or traits-9- or 11-monohydroxy analogues of (
+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12 drobenzo[a]phenanthridine (8a
, dihydrexidine), previously identified as the first full efficacy D-1
dopamine receptor agonist. The monohydroxybenzo[a]phenanthridines wer
e prepared from the appropriately substituted beta-tetralones using th
e methods described earlier for the synthesis of their catechol analog
ues. The 10-bromo 11-hydroxy derivative se was prepared by treatment o
f precursor 9c with bromine in chloroform. The affinities of these com
pounds for the D-1 and De dopamine receptor classes and for their effe
cts on adenylate cyclase activity were assessed in rat striatal membra
nes. In addition to producing only minimal increases in adenylate cycl
ase activity (less than or equal to 15%), these phenolic derivatives g
enerally had significantly lower affinities for D-1 and D-2 receptors
(D-1 IC50 greater than or equal to 102 nM, D-2 IC50 greater than or eq
ual to 210 nM) than did their catechol analogues. Further, compounds b
earing a cis B/C-ring fusion displayed lower affinities than those bea
ring a trans configuration, paralleling the activity differences betwe
en the catechol analogues. The data for these rigid dopamine receptor
ligands from the benzo[a]phenanthridine class lend additional support
for the hypothesis that D-1 agonist activity is optimized by a trans r
ing configuration that maintains the beta-phenyldopamine substructure
in the ''trans-beta-rotamer.''