title: 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.
abstract: Ro 11-2465 (cianopramine, cyan-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 vivo [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 11-2465. 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 (greater than or equal to 0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated 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.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D015283:Citalopram / Q000031:analogs & derivatives; D004347:Drug Interactions; D007099:Imipramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014439:Tyramine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors
chemical_list: D000928:Antidepressive Agents; D011437:Propylamines; C024316:cianopramine; D015283:Citalopram; C001047:4, alpha-dimethyl-3-tyramine; D012701:Serotonin; C046304:desmethylcitalopram; D013973:Thyrotropin-Releasing Hormone; D012110:Reserpine; C046303:cyan-desipramine; D007099:Imipramine; D009638:Norepinephrine; D014439:Tyramine