Abstract
A series of rigid planar azadiindoles (8a, 8b, and 8d), benzannelated pyridodiindoles (11a, lib,
and lid), and indolopyridoimidazoles (11c, 20, and 24) were synthesized from 4-oxo-l,2,3,4-
tetrahydro-jS-carboline 5 via the Fischer indole cyclization with the appropriate arylhydrazines.
Theseanalogueswere employedasprobes(“molecularyardsticks”)todefinethespatialdimensions
ofthelipophilicregionsofthebenzodiazepinereceptor(BzR)bindingcleft. Benzannelatedindoles
lla-d and indolopyridoimidazoles 20 and 24 were important in establishing an area of negative
interaction (Si, see Figure 6, part b) in the binding cleft common to the interactions of both inverse
agonistsandagonists. Datafromthischemicalandcomputer-assistedanalysisofthepharmacophore
(see Figure 6) indicates that inverse agonists and agonists bind to the same binding region, but
the pharmacophoric descriptors required for the two activities are different, in keeping with previous
studieswiththeseplanarligands. However,thehydrogenbonddonatingsiteHiandthelipophilic
region Li in the receptor binding site are common interactions experienced by both series of
ligands. The low affinities of both indolo[3,2-c]carbazole (3a) and indolo[3,2-i>]isoquinoline (3b)
fortheBzRare consonantwiththerequirementsofahydrogenbondacceptorinteractionatdonor
site Hi and a hydrogen bond donor interaction at acceptor site A2 for potent inverse agonist activity
in the d-carboline series. The hydrochloride salts of 1-aza- 8a (IC5010.6 nM), 2-aza- 8b (IC50 51.5
nM), and 4-azadiindole 8d (IC50 11.2 nM) were found to be much more soluble in water than the
corresponding salt of the parent diindole 2. Moreover, aza analogues 8a and 8b were shown to
be partial inverse agonists with proconvulsant potencies comparable to that of the parent diindole 2.