One-pot Synthesis of Chemical Delivery Systems for Gamma-aminobutyric Acid and its Analogues

1. INTRODUCTION

Drug delivery to the central nervous system is a major problem that has long drawn the attention of researchers in various fields [1-3]. The main reason for this is the presence of a specialized cellular structure in blood capillaries, the blood-brain barrier (BBB), which is effectively a semipermeable membrane that excludes most solutes that are present or might be present in the blood [4]. Many polar compounds and those of high molecular weight are unable to diffuse the cellular membrane and many lipophilic molecules that are able to do so are pumped back into the bloodstream as a result of interaction with specialized efflux receptors, such as multidrug resistance proteins [5]. There are several ways to bypass the BBB in order to treat a certain condition. First, with some conditions, such as strokes and cancer, BBB may be (transiently) opened [6]. However, those openings often occur in suboptimal temporal windows and cannot be relied upon for therapeutic needs, for e.g., in the case of ischemic stroke [7], or those do not result in homogeneous drug delivery to the desired areas of the brain [8]. Second, BBB can be disrupted by deliberate physical disturbances, such as ultrasound [9] or hyperosmotic solution [10]. However, this is a risky strategy that involves many side effects from other species found in the blood that enter the brain parenchyma in the absence of a protective barrier [11]. Third, a barrier can be traversed by means of colloidal drug carriers of heterogeneous nature [12]. Finally, there is a chemical approach to drug delivery to the brain. It implies reversibly changing the chemical structure of a drug so that it gains certain qualities that allow it to pass through the BBB, for instance, by making it able to bind to endocytosis receptors (active transport) or by imparting higher lipophilicity while at the same time ensuring that the new molecule will not be a substrate to multiple drug resistance receptors (passive transport) [13]; such modified drugs are known as “prodrugs.” Similar to the prodrug strategy is the concept of chemical delivery systems (CDS), which utilizes known metabolic processes (retrometabolic approach) for site-specific delivery of drugs, and relies on using enzymatic redox reactions to increase their accumulation in the brain parenchyma [14]. Usually, it is achieved by using substrates of NADH dehydrogenase, such as dihydropyridines, which, while reduced, are non-charged and lipophilic, and when oxidized, are charged and more hydrophilic, and thus unable to cross the BBB back into the bloodstream (are “locked-in”) [15].

Usually, such transformations require several steps, especially when dealing with bifunctional molecules, such as amino acids. Therefore, devising a synthetic route that allows obtaining the target compounds with increased yield appears to have practical value. In the past few decades, a one-pot approach for multistage syntheses has been gaining popularity due to its promise of higher yields and relative simplicity [16]. The term “one-pot” refers to a variety of approaches, such as cascade, telescope, domino reactions, etc. For the purposes of this research, by “one-pot”, we mean a telescopic approach to synthesis, one that allows evaporation, extraction, and filtration (with the target compound remaining in solution) without the isolation of intermediate products [17]. This strategy was applied to produce chemical drug delivery systems of gamma-aminobutyric acid and its analogues, and it has resulted in relatively high yields.

2. MATERIALS AND METHODS

Gamma-aminobutyric acid hydrochloride was provided by Acros Organics, gabapentin hydrochloride was purchased from Henan Famo Technology Co., Ltd., and phenibut hydroch- loride was a gift from Mir-Pharm LLC. All other reagents were of the highest quality available, and were used without additional purification. Silica gel (0.04–0.063 mm/230–400 mesh) for column chromatography was purchased from Macherey-Nagel GmbH & Co KG.

3. RESULTS AND DISCUSSION

Retrametabolic drug design in general, and chemical delivery systems in particular, have been applied to various drugs in order to allow them to bypass the BBB [18]. One of the key differences between retrametabolic drug design and more conventional prodrug design is the number of stages a molecule undertakes before being reversed to the original active pharmaceutical compound possessing the necessary therapeutic effect. Therefore, it often means that the original molecule must undergo several steps of chemical modification. Naturally, the most efficient route is desired for the process to be economically and environmentally sound.

In the present study, we have selected several gamma amino acids, such as gamma-aminobutyric acid and its structural analogues, gabapentin and phenibut (Fig. 1), as candidates for modification. Chemical delivery systems have already been obtained for GABA and gabapentin [19, 20], but so far, no such derivatives have been created for phenibut. We foresee that the approach presented here can also be used for other biologically active molecules possessing carboxylic and amine functionalities, such as alpha- and beta-amino acids, short peptides, and other drugs that are not classified as amino acids.

In several studies [19, 20] aimed at the creation of the CDS for gabapentinoids, yields either have not been reported, or in the case of CDS for GABA containing a benzyl moiety [20], have been similar to the one we have obtained in the present study. For the purposes of comparison of the synthetic routes, the method described in the aforementioned papers was recreated in our lab. The former route is presented in Scheme 1.

While facile, this route has several drawbacks, such as low atom economy, use of rather toxic pyridine, and overall low yields (typically in the range of 25 to 35%). The route proposed in this study can be found in Scheme 2. One major concern was its applicability to various alcoholic moieties; therefore, relatively low-boiling alcohols (methanol, n-butanol) and high-boiling alcohols (cyclohexanol, benzylic alcohol) were applied. It was found that the addition of a near-stoichiometric amount of high-boiling alcohol and allowing it to react with acyl chloride under reduced pressure did not significantly lower the overall yield compared to low-boiling alcohols. The slight excess was taken into account in the second stage (amidation with nicotinoyl chloride) by a corresponding increase in the amount of the reagent. This bore little significance at the latter stages, which required a significant excess of reagents.

The yields of the synthesized compounds are given in Table 1.

CONCLUSION

Despite the necessity to purify the final product using chromatography, yields were still higher than those using the conventional synthetic approach. The proposed one-pot synthetic route has allowed us to obtain the target compounds in yields about twice as high compared to the conventional approach, and has also achieved a better atom economy, thus bringing it closer to the compliance with principles of green chemistry. We suggest that the route presented in this study may be used for other compounds bearing dual functionalities, viz., carboxylic and amine groups, such as amino acids and short peptides.

REFERENCES