dm-235 and Amnesia

A series of 2-phenyl- or 3-phenyl piperazines, structurally related to DM235 and DM232, two potent nootropic agents, have been prepared and tested in the mouse passive-avoidance test, to assess their ability to revert scopolamine-induced amnesia. Although the newly synthesized molecules were less potent than the parent compounds, some useful information has been obtained from structure-activity relationships. A small but significant enantioselectivity has been found for the most potent compound 5a.

Topics: Amnesia; Animals; Avoidance Learning; Mice; Nootropic Agents; Piperazines; Pyrroles; Stereoisomerism; Structure-Activity Relationship

A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds.

Topics: Adjuvants, Anesthesia; Amnesia; Animals; Avoidance Learning; Cognition; Drug Design; Mice; Nootropic Agents; Piperazines; Scopolamine; Structure-Activity Relationship; Sulfonamides

Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new compounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease.

Topics: Amnesia; Animals; Avoidance Learning; Chemical Phenomena; Chemistry, Physical; Cognition; Dose-Response Relationship, Drug; Indicators and Reagents; Mice; Muscarinic Antagonists; Neurodegenerative Diseases; Nootropic Agents; Piperidines; Receptors, AMPA; Scopolamine; Structure-Activity Relationship

DM 232 and DM 235 are novel antiamnesic compounds structurally related to ampakines. The involvement of AMPA receptors in the mechanism of action of DM 232 and DM 235 was, therefore, investigated in vivo and in vitro. Both compounds (0.1 mg/kg(-1) i.p.) were able to reverse the amnesia induced by the AMPA receptor antagonist NBQX (30 mg/kg(-1) i.p.) in the mouse passive avoidance test. At the effective doses, the investigated compounds did not impair motor coordination, as revealed by the rota rod test, nor modify spontaneous motility and inspection activity, as revealed by the hole board test. DM 232 and DM 235 reversed the antagonism induced by kynurenic acid of the NMDA-mediated release of [(3)H]NA in the kynurenate test performed in rat hippocampal slices. This effect was abolished by NBQX. DM 232 increases, in a concentration dependent manner, excitatory synaptic transmission in the rat hippocampus in vitro. These results suggest that DM 232 and DM 235 act as cognition enhancers through the activation of the AMPA-mediated neurotransmission system.

Topics: Amnesia; Animals; Avoidance Learning; Cognition; Dose-Response Relationship, Drug; Electrophysiology; Hippocampus; Kynurenic Acid; Male; Mice; N-Methylaspartate; Nootropic Agents; Piperazines; Pyrroles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA