2-Phenyl-imidazo[1,2-a]pyridine Compounds Containing Hydrophilic Groups as Potent and Selective Ligands for Peripheral Benzodiazepine Receptors: Synthesis, Binding Affinity and Electrophysiological Studies

Abstract

A series of imidazopyridine acetamides were synthesized to evaluate the effects of structural changes at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include the introduction of polar substituents or ionizable functional groups at the 2- and 8-position of the imidazopyridine skeleton. The results suggest that substituents endowed with hydrogen bonding acceptor and/or donor properties in the para position of the phenyl ring lead to high affinity for PBR. In electrophysiological studies, it was found that compounds 9, 12, 13, and 28 markedly enhanced GABA-evoked Cl (-) currents in Xenopus oocytes expressing alpha 1beta 2gamma 2 GABA A receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABA A receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion of neurosteroids.

2-Phenylimidazo[1,2-a]pyridine-containing ligands of the 18-kDa translocator protein (TSPO) behave as agonists and antagonists of steroidogenesis in a mouse leydig tumor cell line

“…Our initial efforts were therefore directed to modify the alpidem template in order to increase the selectivity toward TSPO, and the main results of our previous structure-activity relationship studies, combined with a pharmacophore model of TSPO ligands (Anzini et al, 2001), revealed that substituents at the 8-position (Y, Fig. 1), such as for instance Cl (5-8) or NH 2 (9), lead to compounds with enhanced TSPO-selectivity (K i (CBR)/K i (TSPO) > 10 4 ; Denora et al, 2008). In this study we synthesized and assayed for the TSPO/CBR binding affinity two strict analogs of alpidem, compounds 3 and 4, bearing OCH 3 and OH, respectively, as the Z substituents in place of Cl.…”

“…The 2-[6,8-X,Y-substituted-2-(4-Z-substituted-phenyl)imidazo-[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide derivatives 4-10 were synthesized using previously reported procedures (Denora et al, 2008(Denora et al, , 2012Piccinonna et al, 2013;Trapani et al, 1997Trapani et al, , 1999Trapani et al, , 2005. Solvents, chemicals and reagents of analytical grade were purchased from Sigma-Aldrich (Milan, Italy) and used without further purification.…”

“…These experiments were carried out as previously reported by Denora et al (2008). (3) was synthesized according to previously reported procedures (Denora et al, 2012), as outlined in Scheme 1.…”

“…In efforts to differentiate, some of us have synthesized a series imidazo[1,2-a]pyridine-based potent TSPO ligands by introducing on the alpidem structure various substituents at the positions 6 and 8 of imidazo[1,2-a]pyridine nucleus and at the position para of the 2-phenyl group. Since the pioneering work by Trapani et al in the late 1990s on 2-phenylimidazo[1,2-a]pyridine derivatives as TSPO ligands (Trapani et al,1997) a number of promising candidates have been proposed (Denora et al, 2008(Denora et al, , 2014Piccinonna et al, 2013;Trapani et al, 1999Trapani et al, , 2005. In the present study we investigated the ability of a number of imidazo[1,2-a]pyridine-containing TSPO ligands (3-10, Fig.…”

New Fluorescent Probes Targeting the Mitochondrial-Located Translocator Protein 18 kDa (TSPO) as Activated Microglia Imaging Agents

“…More recently, we synthesized the first examples of conjugable imidazopyridinacetamides endowed with high affinity and selectivity for TSPO (18). Although a number of TSPO ligands labeled with 11 C and 18 F have been developed for activated microglia visualization by PET, their short half-life limits their use.…”