Synthesis and pharmacological activity of befuraline (N-benzo[b]furan-2-ylcarbonyl-N'-benzylpiperazine), a new antidepressant compound.
The methods of synthesis and the pharmacological evaluation of a new non-tricyclic antidepressant drug, N-benzo[b]furan-2-ylcarbonyl-N'-benzylpiperazine (befuraline), are reported. The chemical structure of befuraline is clearly different from that of the tricyclic antidepressant drugs. While the gross behavior in animals remains unaffected, the central nervous system depressed by reserpine, tetrabenazine or perphenazine is activated by even small doses of this novel compound. Exploratory activity is prolonged, and performance in operant behavior tests and in the conditioned avoidance response is improved by befuraline, indicating increased alertness, attentiveness and the capacity to react to environmental stimuli. High doses stimulate the CNS, causing EEG desynchronization. Befuraline displays an aggression-inhibiting activity; without having a sedative effect on the animals' normal behavior, it inhibits fighting behavior. The central anticholinergic effect of befuraline is negligible. No apomorphine or tryptamine potentiation is observed and hexobarbital anesthesia is not influenced. The peripheral autonomic nervous system, with the exception of the nictitating membrane in cats, is not affected by befuraline. It has a biphasic effect on the norepinephrine induced contraction of isolated guinea pig seminal vesicle and of isolated cat spleen slices. Although the mechanism of action is as yet not clear, it is assumed that, in addition to a direct influence on the central adrenergic structures, the inhibition of norepinephrine and serotonin uptake and the inhibition of phosphodiesterase are responsible for the drug's effect. Befuraline has no undesirable effects on either the peripheral autonomic nervous system or the cardiovascular system, and it does not affect the normal gross behavior of animals. Because these favorable therapeutic aspects are coupled with low toxicity, befuraline may provide a new alternative in the treatment of depression.
D000818:Animals; D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control; D002375:Catalepsy / Q000517:prevention & control; D002395:Catecholamines / Q000378:metabolism; D002415:Cats; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008996:Monoamine Oxidase Inhibitors; D009119:Muscle Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats
D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D002395:Catecholamines; D008996:Monoamine Oxidase Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines