Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands.
A series of 36 imidazopyridineacetamides (2-37) were designed and synthesized to evaluate the effects of structural changes on the amide nitrogen at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include variations in the length and number of the alkyl groups as well as introduction of different aromatic, heteroaromatic, and conformationally constrained groups. The affinities of these compounds for CBRs and PBRs were determined, and the results indicate that bulkiness of the substituents, their branching, and length beyond an optimal value may cause hindrance to the ligand in its interaction with the receptor. The presence of aromatic or conformationally constrained substituents on the carboxamide nitrogen can be conducive to high affinity and selectivity. Furthermore, the ability of a subset of the most active ligands to stimulate synthesis of neuroactive steroids in plasma and brain was evaluated in vivo and in vitro. Compound 3 exhibited very marked effects on the peripheral and central synthesis of neuroactive steroids, while 36 (potent at subnanomolar level) showed a slight ability to affect neuroactive steroid content in the cerebral cortex.
Trapani
Giuseppe
G
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy. trapani@farmchim.uniba.it
Laquintana
Valentino
V
Denora
Nunzio
N
Trapani
Adriana
A
Lopedota
Angela
A
Latrofa
Andrea
A
Franco
Massimo
M
Serra
Mariangela
M
Pisu
Maria Giuseppina
MG
Floris
Ivan
I
Sanna
Enrico
E
Biggio
Giovanni
G
Liso
Gaetano
G
D000081:Acetamides / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000818:Animals; D001671:Biochemistry / Q000379:methods; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002491:Central Nervous System Agents / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004594:Electrophysiology / Q000379:methods; D005260:Female; D008024:Ligands; D008297:Male; D009584:Nitrogen / Q000737:chemistry; D009865:Oocytes / Q000187:drug effects; D018373:Peripheral Nervous System Agents / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D013256:Steroids / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014981:Xenopus
D000081:Acetamides; D000577:Amides; D002491:Central Nervous System Agents; D008024:Ligands; D018373:Peripheral Nervous System Agents; D011963:Receptors, GABA-A; D013256:Steroids; D009584:Nitrogen