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The in vivo pharmacodynamic and biopharmaceutical characterization of a novel dual mechanism, rapid‐acting antidepressant

Rational design of lead compounds targeting monoamine transporters is critical to developing novel therapeutics for treating psychiatric and substance abuse disorders. A 3‐D dopamine transporter (DAT) computer model was used to virtually screen a small molecule library for high DAT affinity drug‐like compounds. One hit, coded “MI‐4,” inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice (i.p.) induced robust, dose‐dependent antidepressant‐like effects in behavioral models of mood responsive to acute administration (tail suspension and forced swim tests) and chronic administration (novelty‐induced hypophagia test, chronic social‐defeat stress). Importantly, MI‐4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). To facilitate pharmacokinetic analysis, a rapid and highly selective reversed‐phase HPLC method for of MI‐4 was developed and validated according to ICH guidelines. Analysis in human, rat and mouse plasma resulted in a distinct single peak of MI‐4 with USP tailing factor < 2.0 using the MI‐4 analog ifenprodil as an internal standard. The stability of MI‐4 incubated in simulated fasted and fed‐state gastric fluid was 98–100% after 3 hrs and 91–99% after 6 hrs. The Papp value of MI‐4 (0.5 mM) across caco‐2 monolayers after one hour was 33.2×10−6 cm/s, indicating high membrane permeability. Moreover, oral administration (p.o.) of MI‐4 in mice resulted in dose‐ and time‐dependent reductions in tail suspension test immobility scores comparable to the established antidepressants fluoxetine and desipramine, indicating oral efficacy for antidepressant‐like effects. MI‐4 was found to be Ro‐25‐6981, an ifenprodil analog and reputed NMDA antagonist. These data suggest that Ro‐25‐6981, previously known for rapid‐acting antidepressant activity, may also functionally inhibit monoamine reuptake and produce sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining glutamatergic and monoaminergic mechanisms to produce rapid and sustained antidepressant‐like effects.