Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity, and in vivo studies.
The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.
Trapani
G
G
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy. trapani@farmchim.uniba.it
Franco
M
M
Latrofa
A
A
Ricciardi
L
L
Carotti
A
A
Serra
M
M
Sanna
E
E
Biggio
G
G
Liso
G
G
D000818:Animals; D003001:Cloning, Molecular; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011284:Pregnenolone / Q000096:biosynthesis; D011374:Progesterone / Q000096:biosynthesis; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014981:Xenopus
D007093:Imidazoles; D007546:Isoquinolines; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D011374:Progesterone; D011284:Pregnenolone; C037850:PK 11195