The broad objectives of this research program are to develop general methods for promoting the uptake of substances such as neurotransmitters and neuroactive peptides through the """"""""blood- brain barrier"""""""" (BBB). In previous studies we founded that the BBB can be circumvented if a desired molecule was covalently linked to a """"""""transporter molecule"""""""" by an ester bond. Such transporter- coupled compounds behave as """"""""prodrugs"""""""" which release their active moiety after hydrolysis by esterases following entry into the CNS. So far, three such transporters (T) have been identified: (1) glucose, for which the brain has a carrier-mediated transport system, (2) glyceryl lipids, which are normal constituents of lipid bilayer membranes, and (3) cholesterol, which is a prominent component of myelin. We have devised general procedures for the synthesis of T-linked compounds and demonstrated that the brain uptake of molecules such as GABA can be enhanced 100-fold. These methods will be used to synthesize T-linked dopamine, serotonin and peptides such as enkephalin, vasopressin, neurotensin and somatostatin. Their brain uptake, electrophysiological and behavioral pharmacological properties will be evaluated in vivo and vitro to define the size and the molecular characteristics of the transporters that regulate uptake through the BBB. Pilot studies indicate that the uptake of dopamine, serotonin, and 8-Arg vasopressin can be significantly enhanced as glucosyl succinyl derivatives. Such studies may help identify derivatives of dopamine that may provide leads for treatments of Parkinson's disease, enkephalin derivatives that might be useful in treatments of opiate addictions and neurotensin compounds that may be helpful in regulating dopamine release in a number of neuropsychiatric illnesses.
| 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 |
