title: Refinement of the benzodiazepine receptor site topology by structure-activity relationships of new N-(heteroarylmethyl)indol-3-ylglyoxylamides.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Marina
authors.initials: M
authors.lastname: Ehlardo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sala
authors.forename: François
authors.initials: F
authors.lastname: Besnard
authors.forename: Marina
authors.initials: M
authors.lastname: Montali
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: 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
chemical_list: D000577:Amides; D058787:GABA-A Receptor Antagonists; D007211:Indoles; D008024:Ligands