U‐48,753E: A potent, structurally novel antidepressant‐like agent

This is the authors' abstract. We don't add key points for this paper.

U‐48, 753E (trans‐3,4‐dichloro‐N‐(2‐(dimethylamino)‐cyclopentyl)‐propionanilide maleate) was compared to imipramine in a number of tests of antidepressant‐like activity and mechanisms of action. Although not structurally related to imipramine or other nontricyclic antidepressants, U‐48,753E was considerably more potent than imipramine in tests of norepinephrine potentiation, tetrabenazine antagonism, and behavioral despair. U‐48,753E displayed only moderate anticholinergic and no monoamine oxidase inhibitory activities. In vivo measurements of biogenic amine uptake indicated that U‐48,753E blocks norepinephrine, epinephrine, and serotonin uptake and that it is much more potent than imipramine, particularly regarding epinephrine uptake. U‐48,753E is most markedly distinguished by its potency in a test of alpha2‐adrenergic desensitization. Extremely low repeated doses and single doses of U‐48,753E were effective at antagonizing the hypothermia induced by the alpha2 agonist, clonidine. In contrast, imipramine required much higher, repeated doses to display similar activity. The alpha2 desensitization by U‐48,753E is also manifest by a reduced biochemical sensitivity to clonidine; clonidine‐induced slowing of norepinephrine synthesis is antagonized by U‐48,753E pretreatment. Thus, U‐48,753E shares many antidepressant‐like properties with imipramine, but generally has greater potency and a much greater predilection for blocking epinephrine uptake and altering alpha2‐adrenergic sensitivity.