SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF A SERIES OF YDRO-1H-PYRROLO[1,2-A]IMIDAZOLE-2,5(3H,6H)-DIONES, A NOVEL CLASS OF POTENT COGNITION ENHANCERS

A series of hydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones were sy nthesized. These bicylic derivatives contain both the 2-pyrrolidinone and 4-imidazolidinone nuclei, already recognized as important for cogn ition enhancing activity. In addition, these structures maintain the b ackbone of piracetam and oxiracetam with the acetamide side chain rest ricted in a folded conformation. Their ability to reverse scopolamine- induced amnesia was assessed in a one trial, step-through, passive avo idance 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 activit y after po administration. However, the unsubstituted compound (15, di miracetam) 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.