Synthesis and biological investigation of new equatorial (ß) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.

A series of novel 3ß-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.

Studies on the anticonvulsant activity of 4-alkyl-1,2,4-triazole-3-thiones and their effect on GABAergic system.

A series of 4-alkyl-5-(3-chlorobenzyl/2,3-dichlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (1a-14a) were designed, synthesized and screened for their anticonvulsant properties. Moreover, the acute adverse-effect profile of the active compounds (1a-7a, 12a) with respect to impairment of motor performance was evaluated in the chimney test. Among 4-alkyl-5-(3-chlorobenzyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones, ethyl, butyl, pentyl, hexyl, and heptyl derivatives administered intraperitoneally in a dose of 300 mg/kg protected 100% of the tested animals at four pretreatment times (i.e., 15, 30, 60, 120 min). Taking into account the median effective and toxic doses as well as the time-course profile of anticonvulsant activity, 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (4a) was proposed as the best tolerated and the most promising potential drug candidate. Finally, a radioligand binding assay was used to check whether the anticonvulsant activity of 4-alkyl-1,2,4-triazole-3-thiones was a result of their interactions (direct or allosteric) with GABAA receptor complex and/or their affinity to benzodiazepine (BDZ) binding sites.

Studies on the anticonvulsant activity and influence on GABA-ergic neurotransmission of 1,2,4-triazole-3-thione- based compounds.

The anticonvulsant activity of several 1,2,4-triazole-3-thione derivatives on mouse maximal electroshock-induced seizures was tested in this study. Characteristic features of all active compounds were rapid onset of action and long lasting effect. Structure-activity observations showed that the probability of obtaining compounds exerting anticonvulsant activity was much higher when at least one of the phenyl rings attached to 1,2,4-triazole nucleus had a substituent at the para position. The obtained results, moreover, permit us to conclude that despite the structural similarity of loreclezole (second-generation anticonvulsant drug) and the titled compounds, their anticonvulsant activity is achieved via completely different molecular mechanisms.