Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties.
A series of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 10-, and 12-substituted pyridodiindoles were synthesized and screened in vitro against [3H]diazepam for activity at the benzodiazepine receptor (BzR). In vitro, the 2-substituted pyridodiindoles were found to be the most potent (IC50 less than 10 nM) of this new class of BzR ligands. In vivo, 2-methoxypyridodiindole 19a (IC50 = 8 nM) was found to be the most potent partial inverse agonist (proconvulsant) of the series. The parent compound 2 (IC50 = 4 nM) was only slightly less potent. In addition, 2-hydroxypyridodiindole 21a (IC50 = 6 nM) was found to exhibit potent proconvulsant activity when administered as a prodrug derivative, pivaloyl ester 22. 2-Chloropyridodiindole 16a (IC50 = 10 nM) was devoid of preconvulsant activity; however, 16a was found to be the most potent antagonist of the anticonvulsant effects of diazepam in this class of BzR ligands. From the in vivo data available, substitution on ring E of 2 with electron-withdrawing groups results in antagonists at BzR, while replacement of hydrogen at C-2 with electron-releasing groups provides enhanced inverse agonist activity. The pyridodiindoles were used as "templates" for the formulation of a model of the inverse agonist/antagonist active site of the BzR. The proposed model consists of a hydrogen bond acceptor site (A1) and a hydrogen bond donor site (D2) disposed 6.0-8.5 A from each other on the receptor protein. The hydrogen-bonding sites are believed to be located at the base of a narrow cleft. A large lipophilic pocket at the mouth of the narrow cleft serves to direct molecules into the binding site, while the presence of a small lipophilic pocket permits substitution only at position 2 of the pyridodiindole nucleus for maximum binding potency.
Trudell
M L
ML
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
Lifer
S L
SL
Tan
Y C
YC
Martin
M J
MJ
Deng
L
L
Skolnick
P
P
Cook
J M
JM
D000818:Animals; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D003292:Convulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D013329:Structure-Activity Relationship
D003292:Convulsants; D004095:Dihydropyridines; D007211:Indoles; D008024:Ligands; D011963:Receptors, GABA-A