This is a revised application (1 R0l DA09270-OlA1) submitted in response to a medication development program announcement by the National Institute on Drug Abuse (NIDA): PA #90-31/Research Technology. The specific objectives are to develop new tetralin derivatives selective for binding to dopamine D2H (high affinity state) and D3 receptors. These new dopamine receptor binding agents may be useful as tools for the pharmacological evaluation of cocaine addiction and as potential therapeutic agents to target subtypes of """"""""functional"""""""" dopamine receptors, D2H and D3, in countering the reinforcement effects mediated through the dopaminergic system. The project is designed to develop selective D2H and D3 ligands for testing the hypothesis that selective blockage of dopamine receptor subtypes (e.g., D2H and D3 receptors) may provide an effective pharmacological intervention for cocaine addiction. The ultimate goal of this project is to develop medications for the treatment of cocaine addiction. The immediate objective will be limited to the synthesis, optical resolution and screening of a series of new tetralin derivatives with various substitution groups on the tetralin ring, as well as fused cyclic and heterocyclic tetralin ring systems. These new compounds are based on recent success in the development and characterization of a series of iodinated tetralin compounds, such as R(+)trans-7-hydroxy-2- [N-(-3'-iodo-2'propenyl)-N-n-propyl]aminotetralin (R(+)trans-7-OH-PIPAT), which display high affinity to dopamine D2H and D3 receptors (Kd=0.4 nM, rat basal forebrain homogenates). Structure-activity study of the compounds may provide a variety of tetralin derivatives with a set of pharmacophores and structural factors determining the binding affinity and subtype selectivity. In addition to various substitutions on the tetralin rings, optical isomers of these tetralin derivatives will also be evaluated systematically. In the past few years, several tetralin derivatives with stereoselective pharmacological properties, for example, 5-OH and 7-OH-DPAT, have been reported. Each pair of isomers of promising tetralin compounds to be prepared in this project will be tested by in vitro binding studies using [125I]NCQ298, a D2/D3 antagonist, or [125I]R(+)trans-7-OH-PIPAT, a dopamine D2H and D3 ligand, in presence or absence of guanine nucleotides in three different membrane preparations: i) transfected Sf9 cells expressing dopamine D2 and D3 receptors, ii) transfected HEK-293 cell lines expressing guanine nucleotide-sensitive dopamine D2 receptors, and iii) rat basal forebrain homogenates with native dopamine D2 and D3 receptor subtypes. The result of the in vitro binding assays, which are uniquely available in our laboratory, will be used as a guide for further structure-activity evaluations and pharmacological studies of these series of compounds.
| Kung, M P; Stevenson, D A; Zhuang, Z P et al. (1997) Characterization of a novel iodinated ligand, IPMPP, for human dopamine D4 receptors expressed in CHO cells. Life Sci 60:91-100 |
