Effects of the antidepressant pirlindole and its dehydro-derivative on the activity of monoamine oxidase-a and on GABAA receptors

The effects of pirlindole and dehydro-pirlindole on GABA_A receptors and MAO-A activity were investigated in vitro. Pirlindole was inactive as a GABA antagonist. Dehydro-pirlindole exhibited partial and selective blockade of a subset of GABA_A receptors with an EC₅₀ of 12μM and maximum reversal (ΔB_opt) of 42%. Inhibition of rat brain and human placenta MAO-A by both compounds was much more potent (with IC₅₀ range 0.3–0.005 μM). Their effects on MAO-A activity were partially reversible in vitro. In contrast to pirlindole, dehydro-pirlindole may act not only as MAO-A inhibitor but also as a clozapine-like selective GABA_A receptor blocker, preferentially blocking a subset of GABA_A receptors that are not sensitive to DMCM or Ro 5-4864. Pirlindole is the generic name of the drug pyrazidol.     

Molecular docking of inhibitors into monoamine oxidase B

Monoamine oxidase B (MAO-B) functions in the deamination of monoamines, including dopamine and norepinephrine. The search for MAO-B inhibitors increased following the discovery that the enzyme may be responsible for generating neurotoxins from various endogenous or exogenous compounds. Computational screening methods aid in the search for new inhibitors, but validation studies for specific software packages and receptors are necessary for effective application of these methods. In this study, DOCK 6.0.0 was used to dock a series of inhibitors to MAO-B. Included were studies of re-docking ligands into MAO-B crystal structures, after which a set of 30 compounds with known inhibition constants for MAO-B were docked, including 15 strong inhibitors and 15 weak inhibitors. Good agreement was observed between the top experimental inhibitors and the top ranked docking results, and key interactions between the ligands and receptor were identified.