title: Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy. trapani@farmchim.uniba.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Trapani
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.forename: Adriana
authors.initials: A
authors.lastname: Trapani
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.forename: Andrea
authors.initials: A
authors.lastname: Latrofa
authors.forename: Massimo
authors.initials: M
authors.lastname: Franco
authors.forename: Mariangela
authors.initials: M
authors.lastname: Serra
authors.forename: Maria Giuseppina
authors.initials: MG
authors.lastname: Pisu
authors.forename: Ivan
authors.initials: I
authors.lastname: Floris
authors.forename: Enrico
authors.initials: E
authors.lastname: Sanna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
authors.forename: Gaetano
authors.initials: G
authors.lastname: Liso
mesh_terms: 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
chemical_list: D000081:Acetamides; D000577:Amides; D002491:Central Nervous System Agents; D008024:Ligands; D018373:Peripheral Nervous System Agents; D011963:Receptors, GABA-A; D013256:Steroids; D009584:Nitrogen