Amino Acid and Fatty Acid Hydrazides: Chemistry and Action on Monoamine Oxidase

Abstract

Iproniazid (Marsilid") interferes with different enzyme systems. Evidence exists that monoamine oxidase (MAO) inhibition is responsible for some of the actions of the drug in humans, such as the beneficial effectsin mental depression and angina pectoris. On the other hand, the many side effects may also be due to this inhibition, which takes place in a variety of organ systems. I t was believed that, by increasing the organ specificity of the molecule, side effects could be diminished or avoided. Iproniazid Therefore, modification of the alkyl as well as the acyl part of the molecule was carried out as the first step of a research program. This showed that the inhibitory effect on MA0 of hydrazides depends on both the acyl and the alkyl parts of the molecule. The hypothesis was put forward that, by selection of the proper acyl radical, the organ specificity of the hydrazides could be improved. Thus, natural amino acids with a high turnover in a particular organ might carry the active hydrazine molecule to the organ (heart or brain) where action is desired and keep it away from the organ (liver) where it might cause side effects.Evaluation of the potency of the compounds was done by measuring the rise of 5-hydroxytryptamine (5-HT) in rat brain produced by an amount equimolar to 100 mg./kg. iproniazid 16 hours after application. In the following discussions the relative increase of 5-HT as compared to iproniazid will be called the Marsilid index, defined as follows:Increase of 5-HT in rat brain produced by a substance in amount equimolar 100 to 100 mg./kg. iproniazid by 100 mg./kg. iproniazid Marsilid index = ~Increase of 5-€IT in rat brain produced TABLE 1 shows many of the compounds tested that are derived from heterocyclic or aromatic acids. In order to study the effect of variation in the acyl residue, the remainder of the iproniazid molecule (isopropylhydrazine) was left unchanged. No generalization concerning molecular structure and activity could be deduced from the results obtained. TABLE 2 shows some of the compounds having an amino or aliphatic acid as * Hoffmann-La Roche. 555

Designing Prodrugs and Bioprecursors

“…Thus, the l -glutamic analog of iproniazide presents a preferential monoamine oxidase inhibition in the brain, 74 whereas the palmitoyl isopropylhydrazide demonstrates a clear cardiac selectivity ( Table 36.2 ). Systemic site-directed delivery, that is, to a specifi c internal site or organ through a selective transport, is very diffi cult to achieve.…”

Modulation of Reactive Oxygen Species Homeostasis as a Pleiotropic Effect of Commonly Used Drugs

“…Nonetheless, there is no clinical proof that MAO inhibitors reduce levels of toxic and prooxidant MAO products until now ( Tipton, 2018 ). In the clinic, selective MAO-A inhibitors are used as amine-depleting drugs against depression ( Kline, 1958 ; Zeller et al, 1959 ). In contrast, selective MAO-B inhibitors work as dopamine-sparing compounds against PD (selective MAO-B inhibitors) ( Birkmayer et al, 1983 ).…”

Evolution of ideas about the risk of tyramine syndrome developing during therapy with irreversible non-selective monoamine oxidase inhibitors (to the 70th anniversary of the first use of this group of antidepressants)

“…Начиная с конца 50-х гг. специалисты стали обсуждать возможность создания «органоспецифичных» ИМАО [40]. Идея состояла в том, что они должны были влиять на органы, в отношении которых проявляется лечебное действие, например головной мозг или сердце (ИМАО использовались при стенокардии), и быть индифферентными к органам, при воздействии на которые развиваются побочные и токсические эффект, например кишечник и печень (гепатотоксичность).…”