Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.
N-(heteroarylmethyl)indol-3-ylglyoxylamides (1-26) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR) to probe the hydrogen bonding properties of the so-called S(1) site of the BzR by means of suitable heterocyclic side chains. SARs were developed in light of our hypothesis of binding modes A and B. Pyrrole and furan derivatives adopting mode A (2, 8, 10, 20, 22) turned out to be more potent (K(i) values < 35 nM) than their analogues lacking hydrogen bonding heterocyclic side chains. These data suggest that the most potent indoles interact with a hydrogen bond acceptor/donor (HBA/D) group located within the S(1) site of the BzR. Compounds 1, 2, 8, 19, 20, and 22, tested at recombinant rat alpha(1)beta(2)gamma(2), alpha(2)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzRs, elicited selectivity for the alpha(1)beta(2)gamma(2) isoform. On the basis of published mutagenesis studies and the present SARs, we speculate that the S(1) HBA/D group might be identified as the hydroxyl of alpha(1)-Tyr209 or of other neighboring amino acids.
Primofiore
Giampaolo
G
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Da Settimo
Federico
F
Marini
Anna Maria
AM
Taliani
Sabrina
S
La Motta
Concettina
C
Simorini
Francesca
F
Novellino
Ettore
E
Greco
Giovanni
G
Cosimelli
Barbara
B
Ehlardo
Marina
M
Sala
Annalisa
A
Besnard
François
F
Montali
Marina
M
Martini
Claudia
C
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D058787:GABA-A Receptor Antagonists; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D058787:GABA-A Receptor Antagonists; D007211:Indoles; D008024:Ligands