Molecular yardsticks. Rigid probes to define the spatial dimensions of the benzodiazepine receptor binding site.
A series of rigid planar azadiindoles (8a, 8b, and 8d), benzannelated pyridodiindoles (11a, 11b, and 11d), and indolopyridoimidazoles (11c, 20, and 24) were synthesized from 4-oxo-1,2,3,4-tetrahydro-beta-carboline 5 via the Fischer indole cyclization with the appropriate arylhydrazines. These analogues were employed as probes ("molecular yardsticks") to define the spatial dimensions of the lipophilic regions of the benzodiazepine receptor (BzR) binding cleft. Benzannelated indoles 11a-d and indolopyridoimidazoles 20 and 24 were important in establishing an area of negative interaction (S1, see Figure 6, part b) in the binding cleft common to the interactions of both inverse agonists and agonists. Data from this chemical and computer-assisted analysis of the pharmacophore (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 studies with these planar ligands. However, the hydrogen bond donating site H1 and the lipophilic region L1 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-b]isoquinoline (3b) for the BzR are consonant with the requirements of a hydrogen bond acceptor interaction at donor site H1 and a hydrogen bond donor interaction at acceptor site A2 for potent inverse agonist activity in the beta-carboline series. The hydrochloride salts of 1-aza- 8a (IC50 10.6 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.
Martin
M J
MJ
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
Trudell
M L
ML
Díaz Araúzo
H
H
Allen
M S
MS
LaLoggia
A J
AJ
Deng
L
L
Schultz
C A
CA
Tan
Y C
YC
Bi
Y
Y
Narayanan
K
K
D000818:Animals; D001667:Binding, Competitive; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism; D003500:Cyclization; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013698:Templates, Genetic
D002243:Carbolines; D007211:Indoles; D008024:Ligands; D015335:Molecular Probes; D011963:Receptors, GABA-A