N,N-Dialkyl-2-phenylindol-3-ylglyoxylamides. A New Class of Potent and Selective Ligands at the Peripheral Benzodiazepine Receptor

Abstract

We report the synthesis and the affinity data at both the peripheral (PBR) and the central benzodiazepine receptors of a series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamide derivatives III, designed as conformationally constrained analogues of 2-phenylindole-3-acetamides II such as FGIN-1-27. Most of the new compounds showed a high specificity and affinity for PBR, with K(i) in the nanomolar to subnanomolar range. The most potent ligands (4-7, 9, 13-27) stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classical ligands. The SARs of this new class of compounds are discussed.

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

“…The shielding and deshielding of the alkyl carbons of the E and Z isomers are consistent with previous 13 C NMR studies, 31−34 which have shown that alkyl carbon atoms syn to amide oxygen are better shielded than the corresponding anti carbons. In particular, the differential shielding of the N-methyl carbon was attributed either to the electric field caused by the carbonyl group 33,34 or to the paramagnetic contribution of the N−C bond of the N-methyl group.…”

“…Our calculated NMR chemical shifts for Z 1 , Z 2 , E 1 , and E 2 are, nonetheless, very compatible with experimental findings, and thus, we made no attempts to calculate the weighted NMR chemical shifts. The calculated 13 C chemical shifts for Z 1 ′, Z 2 ′, E 1 ′, and E 2 ′ ( Figure S11, Supporting Information) exhibit a pattern similar to those in Figure 2 and are provided for comparison. Figure 10 also depicts a number of possible interconversion paths among the eight rotamers of 1a.…”

“…We therefore calculated NMR chemical shifts for each rotamer since such calculations are known to be very useful for assigning experimental 1 H and 13 C peaks to specific isomers. 30 Figure 3 represents the four rotamers of 1a with their calculated 13 C chemical shifts. For the rotamer identification, we selected four carbons (i.e., N-CH 3 , CHCH 3 , CHCH 3 , and CO) in the amide region because the differential magnetic shieldings of these carbons are stronger than for others.…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…The ligand with the greatest potency from this class was IND-18 ( Fig. 6) with a K i of 0.37 nM, compared to 9.3 nM for PK 11195 in the same binding assay [20]. Twenty of the most potent ligands from this class were evaluated for their ability to stimulate pregnenolone synthesis in rat C6 glioma cells.…”

“…PBR ligands can therefore increase the concentration of neurosteroids in the brain. These neurosteroids, including progesterone, dehydroepiandrosterone and their metabolites, positively modulate γ -aminobutyric acid (GABA) neurotransmission leading to nonsedative anxiolytic effects which are of therapeutic benefit in memory and stress related disorders [20]. Apart from the potential use of PBR ligands in anxiety related disorders, it has been postulated that they could be useful in treating both inflammatory conditions [21,22] and cardiovascular diseases [23].…”