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The aim of the present study was to investigate the biological profile of new substituted 1-phenyl-2-cyclopropylmethylamines. High affinity for both subtypes was achieved when 4-phenylpiperidin-4-ol (4a−e) and 4-benzylpiperidine moieties were present (5a−e). (1R,2S/1S,2R)-2-4-Hydroxy-4-phenylpiperidin-1-yl)methyl-1-(4-methylphenyl)cyclopropanecarboxylate (4b) showed high affinity for the 1sites (Ki1.5 nM) and the most favorable 1/2selectivity (Ki(2)/Ki(1) 33.9). Binding affinity studies showed that 4bbinding on N-methyl-d-aspartate (NMDA), dopaminergic (D1, D2, D3), muscarinic, histaminergic H1, adrenergic (1, 2), serotoninergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT6), DA (DAT), and 5-HT (SERT) transporters was not significant. Interestingly, ligands differently induced the expression of tissue transglutaminase (TG-2) in primary astroglial cell cultures. We suggest that 4bmay act as a 1/2agonist and that the ligands may modulate TG-2 differently. [ABSTRACT FROM AUTHOR]

As an extension of our studies, novel indole derivativeswere rationallydesigned and synthesized as ligands targeted to GluN2B/NMDA receptors.The 2-(4-benzylpiperidin-1-yl)-1-(6-hydroxy-1H-indol-3-yl)ethanone(4i) and 1-(4-benzylpiperidin-1-yl)-2-(6-hydroxy-1H-indol-3-yl)ethane-1,2-dione (6i) showed highbinding affinity in [3H]ifenprodil displacement assay.By computational studies, we suggested the hypothetical interactionsplaying a significant role during the binding process. However, infunctional and in vivo studies the most potent compound 4idid not show any activity whereas it displayed relevant affinitytoward the σ2receptor. [ABSTRACT FROM AUTHOR]