Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect.
OBJECTIVE
Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment.


METHODS
This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure.


RESULTS
The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum.


CONCLUSIONS
Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.
Jamali
Bardia
B
Department of Medicinal Chemistry, School of Pharmacy, Shaheed Beheshti University, Tehran, Iran.
Roodsari
Mahmoodreza Sadeghipoor
MS
Soleymani
Zohre
Z
Faizi
Mehrdad
M
Shafaghi
Bijan
B
Kobarfard
Farzad
F
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000818:Animals; D002626:Chemistry, Pharmaceutical; D018680:Cholinergic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007099:Imipramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008956:Models, Chemical; D053206:Nocturnal Enuresis / Q000188:drug therapy; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
D018680:Cholinergic Antagonists; D000644:Quaternary Ammonium Compounds; D000109:Acetylcholine; D007099:Imipramine