A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants. Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclo[3.1.0]hexane and those with the E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid. The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects. Several derivatives were more active than imipramine and desipramine. On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1-[(diethylamino)carbonyl]-2- (aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development. This compound is currently in phase III clinical evaluation.

A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.

Midalcipran is a new potential antidepressant selected for its equipotent inhibition of noradrenaline and serotonin uptake and its lack of effect at any postsynaptic receptor. In mice it antagonized the depressant effect of tetrabenazine with an oral ED50 value of 0.5 mg/kg as compared to 2.5 mg/kg for desipramine and 5.1 mg/kg for imipramine. Similar findings were obtained for the inhibition of yohimbine-induced mortality. In the "behavioral despair" test, in mice, immobility was significantly reduced by 10 mg/kg midalcipran whereas 20 mg/kg of desipramine was required for a similar effect. Midalcipran enhanced the behavioral changes induced by 1-tryptophan in the rat and antagonized p-chloramphetamine-induced hyperthermia in mice. In contrast to tricyclic antidepressants, midalcipran showed no anticholinergic, sedative or stimulant properties.

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