Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type.
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.
Trapani
G
G
Dipartimento Farmaco-Chimico and Farmaco-Biologico, Facoltà di Farmacia, Università degli Studi di Bari, Italy.
Franco
M
M
Ricciardi
L
L
Latrofa
A
A
Genchi
G
G
Sanna
E
E
Tuveri
F
F
Cagetti
E
E
Biggio
G
G
Liso
G
G
D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D000077334:Zolpidem
D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C028513:4'-chlorodiazepam; D005445:Flunitrazepam; D000077334:Zolpidem