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Pawlowski L, Nowak G, Górka Z, Mazela H.
“Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities”.
Psychopharmacology. 1985;86(1-2):156-163.
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Abstract
Ro 11-2465 (cianoprumhle, cyfln-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these-drugs and their desmethyl metabolites, Ro 12-5419, (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in viva [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro J 1-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (>=0.1 mg/kg). Only Ro 12-5419 , and Ro 11-2465 were able to potentiate the presser response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 patentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyprolledine, that of Ro 12-5419 was counteracted by the NA antigonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4- 16 mg/kg) it had no effect itself but antagonized the stimulutory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT. as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro l 1-2465 and particularly Ro 12-5419 appears to also inhibit the uptake of NA. Moreover. Ro 11-2465 appears to block central and peripheral 5-HT receptors.
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