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Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT 1A R agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT 1A R agonists N -[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate ( rac -1 ) and N -((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1 H -imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate ( rac -2 ) in vitro and in vivo . The role of chirality in the interaction with 5-HT 1A R was evaluated by molecular docking. The activity of the rac -1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac -1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT 1A R antagonist, WAY-100635. The eutomer ( S )- 1 , but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, ( S )- 1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac - 1 . The eutomer ( S )- 1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, ( S )- 1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.

In this study, we applied steered molecular dynamics (SMD) simulations to investigate the unbinding mechanism of nine inhibitors of the enzyme cyclin-dependent kinase 5 (CDK5). The study had two major objectives: (i) to create a correlation between the unbinding force profiles and the inhibition activities of these compounds expressed as IC50 values; (ii) to investigate the unbinding mechanism and to reveal atomistic insights, which could help identify accessory binding sites and transient interactions. Overall, we carried out 1.35 μs of cumulative SMD simulations. We showed that SMD could qualitatively discriminate binders from nonbinders, while it failed to properly rank series of inhibitors, particularly when IC50 values were too similar. From a mechanistic standpoint, SMD provided useful insights related to transient and dynamical interactions, which could complement static description obtained by X-ray crystallography experiments. In conclusion, the present study represents a further step toward a systematic exploitation of SMD and other dynamical approaches in structure-based drug design and computational medicinal chemistry.

As an extension of our studies, novel indole derivatives were rationally designed 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 high binding affinity in [3H]ifenprodil displacement assay. By computational studies, we suggested the hypothetical interactions playing a significant role during the binding process. However, in functional and in vivo studies the most potent compound 4i did not show any activity whereas it displayed relevant affinity toward the σ2 receptor.

The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects.

The aim of the present study was to investigate the biological profile of new substituted 1-phenyl-2-cyclopropylmethylamines. High affinity for both sigma 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 sigma1 sites (Ki = 1.5 nM) and the most favorable sigma1/sigma2 selectivity (Ki(sigma2)/Ki(sigma1) = 33.9). Binding affinity studies showed that 4b binding on N-methyl-d-aspartate (NMDA), dopaminergic (D1, D2, D3), muscarinic, histaminergic H1, adrenergic (alpha1, alpha2), serotoninergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT6), DA (DAT), and 5-HT (SERT) transporters was not significant. Interestingly, sigma ligands differently induced the expression of tissue transglutaminase (TG-2) in primary astroglial cell cultures. We suggest that 4b may act as a sigma1/sigma2 agonist and that the sigma ligands may modulate TG-2 differently.