Synthesis of Chlorinated Tetracyclic Compounds and Testing for Their Potential Antidepressant Effect in Mice

The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively.


Introduction
Depression is the most common psychiatric disorder and is among the 10 leading causes of morbidity and mortality worldwide [1,2]. Recent studies have indicated that depression occurs in all ethnic, racial, and socioeconomic groups and can occur at any age, from childhood to old age. These studies concluded that depression is a common psychiatric disorder in the general population. On an international scale, prevalence estimates of depression are consistently high; varying with population studied and study design. Depression affects more than 340 million people globally [3].
Many of the most common drugs and drug candidates contain halogens. Halogen atoms are often introduced in order to increase lipophilicity, binding affinity and membrane permeability, to fill hydrophobic cavities in the protein binding site, to facilitate the blood-brain barrier crossing and to prolong the lifetime of the drug thereby improves bioavailability [4][5][6][7]. All the selective serotonin reuptake inhibitor (SSRI) antidepressants such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and the very effective top-selling antidepressant drug sertraline possess halogen atoms at specific positions , which are key determinants for the drugs specifity for serotonin transporter (SERT) [7].
The tetracyclic drugs benzoctamine 1-(9,10-dihydro-9,10-ethanoanthracen-9-yl)-N-methylmethanamine and maprotiline 3-(9,10-dihydro-9,10-ethanoanthracen-9-yl)-N-methylpropanamine are bridged anthracene compounds that do not possess halogen atoms [8]. Despite their structural similarity, benzoctamine is primarily an anxiolytic drug that exhibits antagonistic effects on norepinephrine, while maprotiline is an antidepressant and anxiolytic drug that is useful as a norepinephrine uptake inhibitor. Seizures, leukopenia and skin reactions are common side effects of maprotiline. Thus, antidepressants compounds solving the aforementioned problems are desired. Based on the the above evidence, it was decided to synthesis the novel chlorinated maprotiline analogues (5) and (6), since the insertion of a chlorine atoms in the maprotiline related compounds could be a small change for a big improvement aiding in the development of more potent analogues.
tidepressants compounds solving the aforementioned problems are desired. Based on the th ove evidence, it was decided to synthesis the novel chlorinated maprotiline analogues (5) and (6 ce the insertion of a chlorine atoms in the maprotiline related compounds could be a small chang r a big improvement aiding in the development of more potent analogues.

Assessment of Antidepressant Activity Using Forced Swimming Test
To test for the presence of anti-depressant activity of the test compounds (3), (4), (5) and (6). The forced swimming test described previously by David et al. [11] was used with very slightly modification regarding the dimension of the vessel used as a swimming pool. This vessel consisted of a glass cylinder having an internal diameter of 25 cm and water depth of 15 cm and maintained at 22˘2˝C. Swiss white mice weighing 25 g each were divided into 21 groups (n = 4). One group served as control vehicle and the others divided for each test compound and maprotiline.
The test compounds and maprotiline were dissolved in DMSO and examined at 4 dose levels 10, 20, 40, 80 mg/kg (i.p.). The compounds and maprotiline were administered 20 min before starting the swimming test. The control group was administered the vehicle only in the same volume. Each mouse was allowed to stay in the swimming pool for 6 min. Mice normally swim for 1-2 min and then turn helpless and become immobile. An immobile mouse is considered the one that does not show any swimming attempt but shows only movements that allows it to keep its head above the surface of the water. Counting of the time of immobility started at the beginning of the third minutes of placing the mouse into the swimming pool and ended by the end of the sixth minute. In this test antidepressant drugs decrease time of immobility. Thus, for each test compound dose, the time of immobility was calculated. The means˘SEM values were calculated for each group. The data were analyzed using one-way ANOVA followed by Dunnet's multiple comparison test. p < 0.05 was considered to be statistically significant.The percentage decreases in immobility times induced by each doses were calculated.

Conclusions
In conclusion, novel chlorinated tetracyclic compounds were successfully synthesized as analogues of benzoctamine and maprotiline by a simple, economical and flexible three-step formal synthesis from simple and cheap starting materials. The key cyclisation step was accomplished through the Diels-Alder reaction at room temperature. The two target compounds proved to possess potential antidepressant activity as tested by the forced swimming test in mice.