Objectives of the proposed research involve the synthesis of lipophilic prodrug forms of biogenic amine neurotransmitters, determination of the efficacy of these compounds in tests for antidepressant activity in rodents, and determination of structure-activity relationships and the mode(s) of action of active compound. The major objective is to prepare a series of neurotransmitter prodrugs which can penetrate the blood-brain barrier and, after cleavage by enzymes which are present at higher levels in the CNS, replenish brain synaptic levels of norepinephrine, serotonin, and dopamine. According to the biogenic amine theory of depression such compounds might be effective antidepressant drugs.
Specific aims are to: a) synthesize phospholipid prodrugs and urea prodrugs of biogenic amine neurotransmitters; b) to purify the compounds by classical techniques and by HPLC; c) to characterize the compounds by physical properties, elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectrometry, etc; d) to observe the effects of the compounds in tests for antidepressant drug activity in rats and mice. (Tests to be used include reversal of tetrabenazine-induced ptosis and immobilization and potentiation of the effects of L-DOPA.); e) To measure the tendency of active compounds to inhibit monoamine oxidase and to block the uptake of biogenic amines; and f) to determine the structural features responsible for activity by modifying the structures of potent compounds and testing the modified compounds.
| Walsh, B W; Li, H; Sacks, F M (1994) Effects of postmenopausal hormone replacement with oral and transdermal estrogen on high density lipoprotein metabolism. J Lipid Res 35:2083-93 |
