Synthesis and Binding Affinity of 2-Phenylimidazo[1,2-a]pyridine Derivatives for both Central and Peripheral Benzodiazepine Receptors. A New Series of High-Affinity and Selective Ligands for the Peripheral Type

Abstract

A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1,2-alpha]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-alpha]pyridine-3-carboxamides 7a-d,-acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also tested on alpha 2 beta 2 gamma 2s, receptors. However, the EC50 of these compounds was increased, compared to alpha 1 beta 2 gamma 2s receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha 5 subunit.

2‐Phenyl‐imidazo[1,2‐a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

“…However, CB 34 and CB 50 showed no a nity, and CB 54 showed only a low a nity, for central benzodiazepine binding sites labelled by [ 3 H]-¯unitrazepam. These binding data, together with those of a previous study (Trapani et al, 1997), demonstrate that small changes on the pyridine moiety can in¯uence receptor selectivity. Thus, the dichloro substituents at both the 6 and 8 positions of the pyridine moiety of CB 34 and CB 50 appear to confer high a nity and high selectivity for peripheral versus central benzodiazepine receptors.…”

“…Recently, a new class of compounds, 2-phenyl-imidazo[1,2-a]pyridine derivatives, some of which exhibit high a nity for the PBR, were prepared by reaction of the substituted 2-aminopyridines with bromoketoamides (Trapani et al, 1997). We have now investigated the e ects of three of these compounds, termed CB 34, CB 50 and CB 54 (Figure 1), on brain and plasma neurosteroid concentrations in normal and adrenalectomized-orchietomized (ADX-ORX) rats.…”

Major Metabolites of Zolpidem: Expeditious Synthesis and Mass Spectra

“…Substitution on C-3 by a tert-butyl acetate group was completed with tert-butyl diazoacetate/Cu in toluene at reflux. 12,13) By chimioselective acidolysis of the tert-butyl ester of 6 (50% TFA/CH 2 Cl 2 ) 14) carboxylic acid 7 was obtained, and this, in turn, reacted with dimethylamine (peptidic coupling conditions: HBTU, HOBt, DIEA) to give tertiary amide 8. Target carboxylic acid 1 was obtained by saponification of compound 8 with 0.1 N LiOH/THF.…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…In 1997 Trapani and colleagues performed a number of SAR studies on alpidem in attempting to develop a novel range of imidazopyridine derivatives with improved selectivity for the PBR compared to the CBR [65]. As part of these studies, the substituents and acetamide moiety of alpidem were varied whilst maintaining the 2-phenylimidazo[1,2-a]-pyridine heterocyclic ring system.…”