Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potential antidepressant drugs.

A series of eight thienyloxymethylmorpholines, thiophene analogues of viloxazine, have been synthesized by three different routes. The preliminary pharmacological evaluation of this series shows antidepressant properties on the mice models used with a light sedative action. The structure-activity relationship is established in a first approximation.     

Evaluation of thyrotropin-releasing hormone as a potential antidepressant agent in the conscious dog

Results from preliminary clinical reports have indicated that thyrotropin-releasing hormone (TRH) produces improvement in depressed patients. In the present study, doses of TRH at least 25 times greater than those reported as clinically effective on a mg/kg basis were evaluated for antidepressant activity in the conscious dog. Clinically effective antidepressants, such as MAO inhibitors and tricyclics like imipramine, potentiate certain behavioral, autonomic, and cardiovascular responses produced by the indole alkaloid yohimbine, whereas general CNS stimulants such as amphetamine or cocaine do not potentiate these responses. Both 50 and 100 ug/kg doses of TRH failed to potentiate yohimbine effects. Certain gross similarities in effects produced by TRH and amphetamine observed in this study support the view that beneficial effects of TRH in depression may be related to general sympathetic activation produced by this hormone.     

Synthesis and evaluation of new 3-phenylcoumarin derivatives as potential antidepressant agents

A series of amine substituted 3-phenyl coumarin derivatives were designed and synthesized as potential antidepressant agents. In preliminary screening, all compounds were evaluated in forced swimming test (FST), a model to screen antidepressant activity in rodents. Among the series, compounds 5c and 6a potentially decreased the immobility time by 73.4% and 79.7% at a low dose of 0.5 mg/kg as compared to standard drug fluoxetine (FXT) which reduced the immobility time by 74% at a dose of 20 mg/kg, ip. Additionally, these active compounds also exhibited significant efficacy in tail suspension test (TST) (another model to screen antidepressant compounds). Interestingly, rotarod and locomotor activity tests confirmed that these two compounds do not have any motor impairment effect and neurotoxicity in mice. Our studies demonstrate that the new 3-phenylcoumarin derivatives may serve as a promising antidepressant lead and hence pave the way for further investigation around this chemical space.     

Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme

The investigation of a difluoromethyl-bearing nucleoside with the fluorinase enzyme is described. 5′,5′-Difluoro-5′-deoxyadenosine 7 (F₂DA) was synthesised from adenosine, and found to bind to the fluorinase enzyme by isothermal titration calorimetry with similar affinity compared to 5′-fluoro-5′-deoxyadenosine 2 (FDA), the natural product of the enzymatic reaction. F₂DA 7 was found, however, not to undergo the enzyme catalysed reaction with l-selenomethionine, unlike FDA 2, which undergoes reaction with l-selenomethionine to generate Se-adenosylselenomethionine. A co-crystal structure of the fluorinase and F₂DA 7 and tartrate was solved to 1.8 Å, and revealed that the difluoromethyl group bridges interactions known to be essential for activation of the single fluorine in FDA 2. An unusual hydrogen bonding interaction between the hydrogen of the difluoromethyl group and one of the hydroxyl oxygens of the tartrate ligand was also observed. The bridging interactions, coupled with the inherently stronger C–F bond in the difluoromethyl group, offers an explanation for why no reaction is observed.     

Mimosa pudica may possess antidepressant actions in the rat.

In Mexico, aqueous extracts from dried leaves of Mimosa puolica are employed to alleviate depression. In this study, the behavioral actions of aqueous extracts of M. pudica at various concentrations were tested. Rats having received saline (0.9%; 0.30 ml; I.P.), clomipramine, desipramine or several dosages of aqueous extracts from M. pudica (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) during a 30-day period were submitted to the forced swimming test and to the test for differential reinforcement of low rates of response at 72 sec (DRL-72s). Any possible anxiolytic action resulting from several doses (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) of extracts of M. pudica were compared with those caused by diazepam (1.3 mg/kg, I.P.) in the elevated plus-maze test. Results showed that clomipramine (1.25 mg/kg, I.P.), desipramine (2.14 mg/kg, I.P.) and M. pudica (6.0 mg/kg and 8.0 mg/kg, I.P.) reduced immobility in the forced swimming test and increased the rate of reinforcers received in the DRL-72s test; these data suggest that M. pudica produces antidepressant effects in the rat. Diazepam increased the open-arms exploration time in the elevated plus-maze test, but M. pudica did not show any comparable action at any tested dose. M. pudica therefore produced an antide-pressant-like profile similar to two tricyclic antidepressants.     

Alterations in peripheral nerves of rats treated with chlorphentermine or with iprindole

Summary This study deals with the effects of two amphiphilic lipidosis-inducing drugs (chlorphentermine, iprindole) upon the ultrastructure of peripheral nerves of rats. After prolonged drug treatment the preterminal and terminal axoplasm of motor and sensory nerves within skeletal muscles contain numerous abnormal inclusions (osmiophilic conglomerates, autophagic vacuoles, lamellated bodies). By contrast, the axons within large peripheral nerves are little affected. The present observations are tentatively interpreted as resulting from interference with catabolic processes involved in the normal turnover of axoplasmic constituents at the nerve terminal. The exact pathogenesis and the functional significance of these alterations remain to be elucidated.     

Exploration of antimicrobial potential in LAB by genomics

A tremendous flow of information has been created through various genome sequencing projects worldwide. So far, 128 bacterial genome sequences have been completed and 391 are under way. Many of these bacteria, including several lactic acid bacteria (LAB), are used in the production and preservation of food and feed. The major antimicrobial and biopreservative substance produced by LAB is organic acid; however, some LAB produce additional antimicrobial compounds. Among these, the bacteriocins have demonstrated great potential as food preservatives. Additionally, antimicrobial compounds different from the bacteriocins have recently been identified, of which several display strong antifungal activity. The information obtained from genomics and related technologies will have great impact on the future identification and development of new antimicrobial agents. Developments will include the identification of pathways for the production of antimicrobials and genome mining for new antimicrobial peptides.     

Axonal and cellular alterations in the inner ear of rats treated with chlorphentermine or iprindole

An electron-microscopic study was carried out on the inner ear of rats, which had been treated with the anorectic drug chlorphentermine and the antidepressant drug iprindole, two cationic amphiphilic compounds known to induce a generalized lipidosis. After chronic drug treatment the following vestibular and cochlear alterations were observed: a) numerous lamellated and crystalloid cytoplasmic inclusion bodies in various cell types, typical of drug-induced lipidosis; b) axonal balloonings predominantly affecting preterminal sensory endings which were filled with masses of coarse osmiophilic inclusions and autophagic vacuoles. With prolonged treatment degeneration of nerve fibers below the sensory epithelium was observed in increased numbers. Axonal changes are tentatively interpreted to result from drug-induced interference with certain catabolic processes involved in the normal degradation of axoplasmic constituents.