A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and d-cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and d-cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or d-cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and d-cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by d-serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway

New aminoadamantane derivatives with antiproliferative activity

1-Benzyl-2-aminoadamantanes 2a-c, conformationally constrained aminoadamantanes 3a, b and 4 and diaminoadamantanes derivatives 5a-c, 6a-c were synthesized and tested as antiproliferative agents. The in vitro biological evaluation showed a significant difference in activity between 1-phenyl and 1-benzyl derivatives. © Springer Science+Business Media 2013

Synthesis, lipophilicity and biological evaluation of indole-containing derivatives of 1,3,4-thiadiazole and 1,2,4-triazole

3-[(2-Methyl-1H-3-indolyl)methyl]-4-aryl-4,5-dihydro-1H-1,2,4-triazole- 5-thiones 6a-c and their respective N-5-[(2-methyl-1H-3-indolyl) methyl] - 1,3,4-thiadiazol-2-yl -N-arylamines 7a,b have been prepared. The antidepressant profile of 6a,c and 7a was studied on mice with respect to that of the analogous 3-(1H-1-indolylmethyl)-4-aryl-4,5-dihydro- 1H- 1,2,4- triazole-5-thiones 1a-c and the respective N- 5 [(2-methyl-1H-3- indolyl)methyl]-1,3,4-thiadiazol-2-yl-N-arylamines 2a-c, the synthesis and antimicrobial potency of which we have recently reported. Behavioral effects, induced by the members of both series, in conjunction with their activity in some specific tests (forced swim, pentetrazole convulsions) on mice, show that these derivatives cross the blood-brain barrier and could develop an antidepressant activity comparable to that of imipramine. Blood-brain barrier penetration is also supported by the lipophilicity data obtained for all analogs

The neurochemical effects on striatal dopamine turnover rate of N-stearyl dopamine, after acute administration in rats

1. Considerable efforrts have been made in order to develop autoreceptor selective agonists for the treatment of schizophrenia and hyperkinetic disorders. 2. Recent behavioural studies showed that the newly synthesized dopamine lipoamide, N-stearyl dopamine induced a strong hypomotility (-80%) in rats and mice. It is worth noting that this behavioural response was partially antagonized by dopaminergic antagonists, such as haloperidol and sulpiride, administered at doses that block DA autoreceptors. 3. In the present study the authors investigated the neurochemical changes induced by S-DA, in the striatum of the rat brain, in order to estimate a possible correlation between the above mentioned behavioural response and DA metabolism. 4. S-DA (10 or 100mg/kg, i.p.) induced a significant decrease in DA turnover rate while it did not affect 5-HT metabolism in the striatum. 5. Considering that S-DA induces a strong hypomotility, which can be partially antagonized by haloperidol or sulpiride administered at low doses, while also decreases the striatal DA turnover rate, it could be suggested that together these findings indicate that this DA lipoamide may be display the characteristics of an antipsychotic agent, acting on the "DA selective" autoreceptors

The novel GABA adamantane derivative (AdGABA): Design, synthesis, and activity relationship with gabapentin

A facile preparation of 2-aminomethyl-2-tricyclo[3.3.1.1 1,7]decaneacetic acid hydrochloride 5 (AdGABA) is described. The synthesis of AdGABA involves the hydrogenation of 2-cyano-2-tricyclo[3.3.1. 11,7]decaneacetic acid 11, which was synthesized by two different synthetic routes. AdGABA was found to antagonize the pentylenetetrazole (PTZ) and semicarbazide (SCZ) induced tonic convulsions and exhibits analgesic activity in the hot plate test on mice. Although its mechanism of action is quite similar to that proposed previously for gabapentin (interaction with the α2δ subunit of the voltage gated Ca2+ channels), further studies were undertaken in order to clarify the precise mechanism of the anticonvulsant and analgesic effects of AdGABA on a molecular level. © 2005 Elsevier Ltd. All rights reserved

New adamantane derivatives with sigma affinity and antiproliferative activity

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6- diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs. © 2012 Bentham Science Publishers