Synthesis of novel 3-substituted beta-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore.
The 3-substituted beta-carbolines 2-4 and 5-7 were prepared from 3-amino-beta-carboline (8) in one step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their binding affinity for benzodiazepine receptors (BzR). All three of the 3-alkoxy-beta-carbolines 2 (IC50 = 124 nM), 3 (IC50 = 24 nM), and 4 (IC50 = 11 nM) have high affinities for BzR. The beta-carbolines substituted with electron-withdrawing groups including 5 (Cl; IC50 = 45 nM), 6 (NO2; IC50 = 125 nM), and 7 (N = C = S; IC50 = 8 nM) also had high affinities for BzR. The affinities of 5-8 clearly indicate that a carbonyl moiety at position 3 of a beta-carboline is not required for high-affinity binding to BzR. These findings have led to the development of a model for the binding of ligands to an inverse agonist domain at BzR. This model is supported by the recent synthesis of 3-ethoxy-beta-carboline (3), a potent, long-lived partial inverse agonist, and 7, an irreversible BzR ligand.
Allen
M S
MS
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
Hagen
T J
TJ
Trudell
M L
ML
Codding
P W
PW
Skolnick
P
P
Cook
J M
JM
D000818:Animals; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003975:Diazepam / Q000378:metabolism; D006860:Hydrogen Bonding; D007211:Indoles; D051379:Mice; D011725:Pyridines; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D002243:Carbolines; D007211:Indoles; D011725:Pyridines; D011963:Receptors, GABA-A; D003975:Diazepam