The broad objectives of this research program are to devise procedures which will allow substances such as neurotransmitters and peptides to penetrate the """"""""blood-brain barrier"""""""" (BBB). In preliminary studies we found that the uptake of Gamma-aminobutyric acid (GABA) can be increased from 1% up to 100% if the molecule is covalently bound by an ester bond to a """"""""transporter molecule"""""""" which takes it through the BBB and releases it by hydrolysis after entry into the CNS. Two classes of """"""""transporter molecules"""""""" have been identified: (1) those such as glucose (G) for which there exists a special uptake system in the CNS, and (2) those which are normal constituents of the bilipid layer of neuronal membranes, such as cholesterol (C) and dilinolenoyl glyceride (L-G). We will synthesize general reagents based on G, C, and L-G which contain anhydride functional groups suitable for forming esters and amide bonds with substances containing -OH and -NH2 groups and investigate their capacity to act as transporter molecules. These reagents will be used to prepare derivatives of radiolabeled and unlabeled GABA, dopamine, serotonin and peptides such as met-enkephalin and vasopressin to investigate the classes and sizes of molecules that can be transporter across the BBB by the procedure. The uptake of each compound will be studied using the """"""""brain penetration index"""""""" assay procedure. This compares brain with liver as the standard. In vitro physiological activity of the GABA and serotonin derivatives will be tested on the hippocampal slice preparation. The magnitude and duration of inhibitory effects of delivering pico molar amounts via a micropipette on the response of pyramidal cells of hippocampus to stimulation will be measured. Such data will be correlated with the rate of release of the active moiety of each molecule by hydrolysis using brain homogenates and subcellular fractions as enzyme sources. In vivo tests in rats of the most promising compounds will also be carried out. Such studies will help define the fundamental properties of transporter molecules and procedures for uptake through the BBB. The research should aid in the search for pharmacological agents for treatments of neuropsychiatric illnesses where a deficiency of neurotransmitter and peptide levels exists in the CNS, such as in epilepsy and Parkinson's disease, where GABA and dopamine are low. In addition, the vasopressin derivative may be useful in improving memory problems in aging.
| Jacob, J N; Hesse, G W; Shashoua, V E (1990) Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor gamma-vinyl-GABA. J Med Chem 33:733-6 |
| Backus, L I; Stellar, J R; Jacob, J et al. (1988) Novel GABA agonists depress the reward effect of lateral hypothalamic stimulation in rats. Pharmacol Biochem Behav 30:657-63 |
| Hesse, G W; Jacob, J N; Shashoua, V E (1988) Uptake in brain and neurophysiological activity of two lipid esters of gamma-aminobutyric acid. Neuropharmacology 27:637-40 |
| Jacob, J N; Hesse, G W; Shashoua, V E (1987) gamma-Aminobutyric acid esters. 3. Synthesis, brain uptake, and pharmacological properties of C-18 glyceryl lipid esters of GABA with varying degree of unsaturation. J Med Chem 30:1573-6 |
