SYNTHESIS AND MOLECULAR MODELING OF 1-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLINES AND RELATED 5,6,8,9-TETRAHYDRO-13BH-DIBENZO[A,H]QUINOLIZINES AS D-1 DOPAMINE ANTAGONISTS
Dl. Minor et al., SYNTHESIS AND MOLECULAR MODELING OF 1-PHENYL-1,2,3,4-TETRAHYDROISOQUINOLINES AND RELATED 5,6,8,9-TETRAHYDRO-13BH-DIBENZO[A,H]QUINOLIZINES AS D-1 DOPAMINE ANTAGONISTS, Journal of medicinal chemistry, 37(25), 1994, pp. 4317-4328
New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetra
hydro-13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted
analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e
.g., SCH23390) as a continuation of our studies to characterize the an
tagonist binding pharmacophore of the D-1 dopamine receptor. Receptor
affinity was assessed by competition for [H-3]SCH23390 binding sites i
n rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline a
nalog 2 of SCH23390 1 had D-1 binding affinity similar to that for the
previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy anal
og 5 had significantly lower D-1 affinity. Conversely, neither 6-monoh
ydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had
significant affinity for the D-1 receptor. These results demonstrate t
hat 6-halo and 7-hydroxy substituents influence D-1 binding affinity o
f the 1-phenyltetrahydroisoquinolines in a fashion similar to their ef
fects on 1-phenyltetrahydrobenzazepines. azepines. The conformationall
y constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had muc
h lower affinity relative to the corresponding, and more flexible, 6-c
hloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihyd
roxytetrahydrodibenzoquinolizine 10 had much lower D-1 affinity compar
ed to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenan
thridine that is a high-affinity full D-1 agonist. Together, these dat
a not only confirm the effects of the halo and hydroxy substitutents o
n the parent nucleus but demonstrate the pharmacophoric importance of
both the nitrogen position and the orientation of the accessory phenyl
ring in modulating D-1 receptor affinity and function. Molecular mode
ling studies and conformational analyses were conducted using the data
from these new analogs in combination with the data from compounds pr
eviously synthesized. The resulting geometries were used to refine a w
orking model of the D-1 antagonist pharmacophore using conventional qu
antitative structure-activity relationships and three-dimensional QSAR
(CoMFA).