Anxiolytic activity of a brain delivery system for GABA

Abstract

We evaluated the anxiolytic property of a brain-specific gamma-aminobutyric acid delivery system (GABA-CDS) in male rats by means of a drink-foot shock conflict procedure. Brain-specific delivery of the active compound was achieved by combination of GABA benzyl ester with an interconvertible dihydropyridine in equilibrium pyridinium salt carrier, which is "locked in" to the brain upon its oxidation. Pharmacokinetic studies revealed that the hydrophilic pyridinium salt form (G-Q+) of the GABA-CDS formed in situ remained in the brain for 12 h but was cleared from the blood and other peripheral tissues by 0.5-4 h. While the lipophilic form (G-DH) of the GABA-CDS caused a marked and sustained anxiolytic response when administered systemically, GABA and the charged pyridinium salt (G-Q+ form) of the GABA-CDS were ineffective. G-DH was injected at either 0, 4, 10 or 25 mg/kg IV in DMSO after rats were water and food deprived. After either 0.5, 2, 4, 8 or 24 h, rats were permitted 10 s of shock-free drinking of 10% sucrose, then given a 35 mA (DC) current through the drinking tube. Drinking time was recorded for 3 min. All doses of G-DH caused a significant increase in anxiolysis over control levels through 8 h. An increase (4 to 7-fold) in anxiolytic activity was observed through the 10 mg/kg dose with the 25 mg/kg dose causing no additional increase. No sedation or analgesia was observed at 2 h with any anxiolytic-producing dose of G-DH. These results suggest that G-DH elicits anxiolysis with minimal sedation, through the local brain action the G-Q+ or subsequent to the release of GABA.

Synthesis and biological evaluation of GABA derivatives able to cross the blood–Brain barrier in rats

“…Mass spectrometry and 1 H NMR allowed the identification of both 1 and 2 as symmetric dimers formed by coupling of the radicals resulting from the one electron reduction of 1a and 2a respectively. In particular the 1 H NMR data were consistent with 1,4-dihydronicotinamide structures, as confirmed also by comparison with 1 H NMR spectrum of 3, 6 and, furthermore, the presence of methine hydrogen signals at d=3.36 for 1 and d=3.26 for 2, unambiguously indicated carbons 4 as coupling sites of the dihydronicotinamide moieties. 9,10,18,19 From the dimerization of the pyridinyl radicals which gives rise to 1 and 2, two equivalent centers of asymmetry are formed at the junction carbons; therefore, two diastereoisomers, a meso form (R,S) and a racemate (RR and SS) are possible in both cases.…”

“…3,4 To this purpose, many researches have been devoted to the synthesis of GABA-prodrugs, such as GABA esters and amides, 5 more lipophilic than the parent molecule and able to cross the blood-brain barrier and deliver and release into the brain the neurotransmitter. In this context, a useful GABA brain-specific delivery system, which showed a significant anxiolytic activity, has been developed by Anderson et al 6 using a lipophilic 1,4-dihydronicotinamide derivative of the bioactive molecule (structure 3, Fig. 1).…”

Targeting drugs to the brain by redox chemical delivery systems

“…CDSs for 17 (19a,b) have been developed, along with compounds for the brain-targeting of a redox analog (18). 85,86 Unlike for 11, earlier studies indicated that hydrolysis to the neurotransmitter was unnecessary for GABAergic activity. 87 CNSdelivery by 19,22, and 23 is shown schematically in Fig.…”

“…Concentrations of Benzylpenicillin(85) in Rabbit Blood, Brain, and CSF after i.v. Administration of 10 mg/kg 85 or Equimolar Doses of CDSs 86a and 86bConcentration of 85 (mg/ml or mg/g)…”

Evidence for Prolonged Suppression of Stress-Induced Release of Adrenocorticotropic Hormone and Corticosterone with a Brain-Enhanced Dexamethasone-Redox Delivery System

“…This method of delivery is based upon a dihydropyridine ^ pyridi nium salt redox system which has been demonstrated to accom plish brain-enhanced drug delivery when applied to a number of pharmacologically active species including phenethylamine [5], dopamine [6], y-aminobutyric acid [2], testosterone [7], and estradiol [1,3,8,13,29].…”