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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.

Current antipsychotic drugs are notably ineffective at addressing the cognitive deficits associated with schizophrenia. N -Desmethylclozapine (NDMC), the major metabolite of clozapine, displays muscarinic M 1 receptor (M 1 ) agonism, an activity associated with improvement in cognitive functioning. Preclinical and clinical data support that M 1 agonism may be a desired activity in antipsychotic drugs. However, NDMC failed clinical phase II studies in acute psychotic patients. NDMC analogues were synthesized to establish a structure-activity relationship (SAR) at the M 1 receptor as an indication of potential procognitive properties. In vitro evaluation revealed a narrow SAR in which M 1 agonist activity was established by functionalization in the 4- and 8-positions in the tricyclic core. In vivo behavioral response profiles were used to evaluate antipsychotic efficacy and exposure in zebrafish larvae and peripheral side effect related M 1 activity in adult zebrafish. The NDMC analogue 13f demonstrated antipsychotic activity similar to clozapine including M 1 agonist activity. Cotreatment with trospium chloride, an M1 peripheral acting antagonist, counteracted peripheral side effects. Thus, the NDMC analogue 13f , in combination with a peripherally acting anticholinergic compound, could be suitable for further development as an antipsychotic compound with potential procognitive activity.