Enantioselective synthesis and preliminary pharmacological evaluation of the enantiomers of unifiram (DM232), a potent cognition-enhancing agent.
The enantiomers of the potent cognition-enhancer DM232 ((1), unifiram) and of its isopropylsulfonyl analog (2), which is endowed with amnesic properties, have been synthesized using (S)- and (R)-5-(hydroxymethyl)-2-pyrrolidinone as chiral precursors. The enantiomeric excess was determined by means of capillary electrophoresis, and found higher than 99.9 %. DM232 enantiomers were tested as cognition-enhancers in the passive-avoidance and social learning tests, and their ability to induce ACh release from rat cerebral cortex was also determined; in all the performed essays, (R)-(+)-(1) displayed higher potency than its (S)-(-) enantiomer, being able to elicit comparable effects at 3-fold to 10-fold lower doses. On the contrary, (R)-(+) and (S)-(-)-(2) showed the same amnesic potency when tested in the passive-avoidance test. These findings may be useful to clarify the mechanism of action of these substances.
Martini
Elisabetta
E
Dipartimento di Scienze Farmaceutiche, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
Ghelardini
Carla
C
Bertucci
Carlo
C
Dei
Silvia
S
Gualtieri
Fulvio
F
Guandalini
Luca
L
Manetti
Dina
D
Scapecchi
Serena
S
Teodori
Elisabetta
E
Romanelli
Maria Novella
MN
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D018697:Nootropic Agents; D010879:Piperazines; D011758:Pyrroles; C409868:DM 232