title: Synthesis and pharmacological activity of a series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, a novel class of potent cognition enhancers.
abstract: A series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones were synthesized. These bicylic derivatives contain both the 2-pyrrolidinone and 4-imidazolidinone nuclei, already recognized as important for cognition enhancing activity. In addition, these structures maintain the backbone of piracetam and oxiracetam with the acetamide side chain restricted in a folded conformation. Their ability to reverse scopolamine-induced amnesia was assessed in a one trial, step-through, passive avoidance paradigm. The main features observed are a potent antiamnestic activity after ip administration (minimal effective dose being between 0.3 and 1 mg/kg ip for most compounds), the presence of a bell-shaped dose-response curve and, generally, a reduction of biological activity after po administration. However, the unsubstituted compound (15, dimiracetam) shows no evidence of a bell-shaped dose-response curve and completely retains activity when given orally, being 10-30 times more potent than the reference drug oxiracetam.
authors.affiliation: SmithKline Beecham Farmaceutici, Research Laboratories, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pinza
authors.forename: C
authors.initials: C
authors.lastname: Farina
authors.forename: A
authors.initials: A
authors.lastname: Cerri
authors.forename: U
authors.initials: U
authors.lastname: Pfeiffer
authors.forename: M T
authors.initials: MT
authors.lastname: Riccaboni
authors.forename: S
authors.initials: S
authors.lastname: Banfi
authors.forename: R
authors.initials: R
authors.lastname: Biagetti
authors.forename: O
authors.initials: O
authors.lastname: Pozzi
authors.forename: M
authors.initials: M
authors.lastname: Magnani
authors.forename: L
authors.initials: L
authors.lastname: Dorigotti
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010889:Piracetam / Q000737:chemistry; D011487:Protein Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D011758:Pyrroles; D011759:Pyrrolidines; C085079:dimiracetam; D012601:Scopolamine; C040619:oxiracetam; D010889:Piracetam