.gamma.-Aminobutyric acid esters. I. Synthesis, brain uptake, and pharmacological studies of aliphatic and steroid esters of .gamma.-aminobutyric acid

Abstract

Labeled and unlabeled aliphatic and steroid esters of gamma-amino[U-14C]butyric acid (GABA) were synthesized and tested for their capacity to penetrate the blood-brain barrier and for evidence of central neuropharmacological activity in rodents. The uptake of the labeled 9,12,15- octadecatrienyl ( linolenyl ), 3-cholesteryl, 1-butyl, and the 9-fluoro-11 beta,17-dihydroxy-16 alpha-methyl-3,20- dioxopregna -1,4-dien-21-yl (dexamethasone) esters of GABA into mouse brain increased 2-, 25-, 74-, and 81-fold over GABA, respectively. The cholesteryl ester of GABA depressed the general motor activity of mice and rats in a dose-dependent manner, whereas the 1-butyl, linolenyl , and dexamethasone esters were inactive by this test. Studies of the rates of hydrolysis, GABA receptor binding capacity, and octanol/water partition coefficients indicated that pharmacological activity of the esters after entry into the central nervous system (CNS) was dependent on their capacity to release GABA by enzymatic hydrolysis and their lipid solubility.

Chiral Ionic Liquids Bearing O‐Silylated α,α‐Diphenyl (S)‐ or (R)‐Prolinol Units: Recoverable Organocatalysts for Asymmetric Michael Addition of Nitroalkanes to α,β‐Enals

“…[2] Unfortunately, GABA itself is inefficient for therapeutic purposes due to its hydrophilic behavior that prevents its penetration through the blood-brain barrier. [3] Thereby GABA lipophilic derivatives are commonly used for the treatment of CNS disorders. [4] Among them, Baclofen, [5] Rolipram, [6] Pregabalin, [7] and Phenibut [8] have found wide application.…”

High Fibre Diets and Alzheimer’s Disease

“…Animal studies will be helpful to understand this combination while human studies are required to identify its long term effects. On the other hand, aliphatic and steroid esters of gamma-amino [U-14C] butyric acid (GABA) which is a synthesized compound have proved to have a high penetration capacity across the blood brain barrier [158].…”

Design, Synthesis, and Potent Antiepileptic Activity with Latent Nerve Rehabilitation of Novel γ-Aminobutyric Acid Derivatives

“…[29][30][31][32][33][34][35] These observations raise the possibility that "replacement" procedures that increase GABA level of central nervous system (CNS) may be useful in the treatment of such neuropsychiatric disorders. 36) Nevertheless, most of antiepileptic drugs including GABA analogues have proven to be discontented as they have little effect on the prognosis of patients with intractable epilepsy due to the lack of potential capacity to rehabilitate the nerve nidus or prevent seizure from injuring neuronal cells. Simultaneously, clinical treatment of epilepsia with GABA is impractical because the present results illustrate that bloodbrain barrier (BBB) in adult animals is impermeable to both blood-borne GABA and endogenous cerebral GABA owing to the low lipophilicity (log P=−0.82) (P: partition coefficient).…”