Anna Sławińska

The antipsychotic‐like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents

Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain‐penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents.

Anxiolytic-like activity of zinc in rodent tests

Because zinc deficiency induces depression and anxiety-like behavior in rodents, we examined the effects of zinc administration in several tests by measuring anxiolytic activity in mice and rats. We now report that zinc significantly increased the number of entries into the open arms in the elevated plus maze in rats. Moreover, zinc treatment significantly increased the number of punished crossings in the four-plate test and attenuated stress-induced hyperthermia (SIH) in mice. However, no effect of zinc administration was observed in the elevated plus maze test in mice. This lack of effect in the latter case was probably due to the substantial zinc-induced reduction in locomotor activity by the doses used in mice. The present data demonstrate for the first time the anxiolytic-like activity of zinc in rodents and may indicate that zinc could be used as a novel therapeutic/adjunct agent in anxiolytic therapy.

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: part 2.

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT(1A) receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT(1A) receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT(1A) receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with -OCH(3) or -F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT(1A) receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.