In mice, yohimbine appears to accentuate the normal " alarm " reactions (alerting, flight) to external stimuli. Imipramine increases this effect and at the same time converts a non-lethal dose of yohimbine into a lethal one. The effect of imipramine is greatly reduced by adrenalectomy or by treatment with reserpine, syrosingopine, ganglion-blocking drugs or adrenaline antagonists acting on sympathetic 3-receptors. Hypnotic, anti-convulsant or anaesthetic agents, tetrabenazine or antagonists of 5-hydroxytryptamine do not reduce the imipramine effect. A variety of drugs which, like imipramine, are known to interfere with the tissue binding of noradrenaline also increase the toxicity of yohimbine. Yohimbine significantly reduces brain noradrenaline content; adrenal catechol amines are slightly reduced. The results suggest that yohimbine releases noradrenaline from stores or nerves as a consequence of increased central sympathetic activity. Imipramine increases the actions and toxicity of yohimbine by increasing the effects of the released noradrenaline on 1-receptors.The lethal effects of a high dose of yohimbine alone are not reduced by any of the treatments tested, and appear not to result from activation of sympathetic mechanisms.

Seven structurally-related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine. have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine-induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine-induced bradycardia in rats offer further evidence for drug-induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs.

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Analogs of Imipramine 255 5-(2-Diethylaminoethyl)dibenzo [a,d] cycloheptadiene-5-carboxamide.-A mixture of the carbonitrile (no. 1A) (15.0 g., 0.042 mole) and 90% sulfuric acid (30 ml.) was heated on the steam bath with stirring for 3 hr. It was cooled, poured into ice and water, and the mixture made alkaline with sodium hydroxide. The product was collected in chloroform and the organic layer was dried and evaporated. The residue was converted to the oxalate salt which was recrystallized from ethanol-ether, m.p. 161-162°d ec. (12.2 g., 69% yield) (see Table II, no. 9). 5-(-A solution of the pyrrolidide (8.3 g., 0.028 mole) in dry toluene (50 ml.) was added to sodium hydride (53.8% dispersion; 1.45 g., 0.032 mole) suspended in toluene (50 ml.). The mixture was stirred and heated under reflux for 4 hr., during which time a precipitate formed and an orange color developed. A solution of 2-chloroethylmorpholine (6.7 g., 0.045 mole) in toluene (50 ml.) was added dropwise and heating was continued for an additional 1 hr. The mixture was filtered while hot and the solution was extracted with dilute hydrochloric acid. The aqueous layer was extracted with ether, made alkaline and the oil was taken up in benzene. Evaporation of the solvent left the product as a solid; needles from petroleum ether (b.p. 80-100°) or ethyl acetate-hexane, m.p. 148-149°( 4.4 g., 38% yield)Removal of the Cyano Group.-A suspension of sodium amide (2.3 g., 0.06 mole) in xylene (100 ml.) was treated with the free base V (5.1 g., 0.015 mole) and the mixture was stirred and heated under reflux for 16 hr. It was cooled, treated with water, and the organic layer was extracted with dilute hydrochloric acid. The acidic layer was made alkaline and the product was collected in benzene. Evaporation of the solvent gave 1.1 g. (87% yield) of IX; the hydrochloride, m.p. 185-187°, was identical with an authentic sample.2

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