This proposal presents, for synthesis and pharmacological evaluation, series of 2-aminoindans, enantiomers of alpha-ethyltryptamines, certain benzofuran congeners, and [125I]-labeled analogs of the novel psychoactive agent 3,4-methylenedioxymethamphetamine (MDMA). Structures are based upon our previous findings that certain alpha- ethylphenethylamines and rigid analogs of MDMA possess animal behavioral pharmacology similar to MDMA, but have attenuated dopaminergic properties and decreased serotonin neurotoxicity. The target structures will serve as pharmacological tools for several purposes: to aid in elucidation of the mechanism of action of MDMA, to further refine the structure-activity relationships of MDMA-like drugs, to study certain components of the neurotoxic effects of MDMA-like agents, and to be used to help elucidate the role of serotonin in certain behavioral states. In particular, following synthesis, new compounds will be tested for MDMA-like behavioral pharmacology using the two-lever drug discrimination paradigm, in rats trained to discriminate saline form the alpha-ethyl homolog of MDMA,(+)-MBDB. Compounds which fully substitute will then be examined for ability to inhibit uptake or effect release of serotonin (5-HT), dopamine, or norepinephrine from rat brain synaptosomes. Compounds showing high selectivity for 5-HT will be further evaluated for acute in vivo effects on brain monoamine and metabolite levels. After multiple dosing with these compounds and sacrifice at 1-week, examination of brain monoamines, their metabolites, and radioligand binding parameters using the 5-HT uptake inhibitor [3H]- paroxetine, will be used as indicators of serotonin neurotoxic potential. Compounds will be evaluated for reinforcing properties using the conditioned place preference paradigm. Compounds which do not induce place preference will be tested for their ability to antagonize (+)-amphetamine-induced place conditioning, as potential antagonist of the reinforcing properties of psychostimulants. Formal collaborative arrangements have been developed with five other laboratories to study further new compounds for locomotor activating effects in rats, ability to increase extracellular dopamine measured by in vivo microdialysis, and the radiosynthesis and use of certain neurotoxic and nonneurotoxic [125I]-ligands to visualize 5-HT neurons in rat brain. Also through a collaborative arrangement, compounds that block amphetamine-induced place preference will be tested for an ability to antagonize the reinforcing effects of cocaine in rats that intravenously self- administer cocaine.
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