SYNTHESIS, RESOLUTION AND RADIOIODINATION OF DO-2'-PROPENYL)AMINO]TETRALIN-S(-)TRANS-5-OH-PIPAT - NEW DOPAMINE D2-LIKE RECEPTOR-LIGAND

A new dopamine D2-like receptor ligand, -[N-n-propyl-N-(3'-iodo-2'-pro penyl)amino]tetralin ((R,S)trans-5-OH-PIPAT, (3) under bar), based on high affinity dopamine receptor agonist 5-hydroxy-2-[N,N-(di-n-propyl) -2-amino]tetralin (5-OH-DPAT, (1) under bar), was prepared. The synthe sis was achieved by a reductive amination of 5-methoxy-2-tetralone wit h n-propylamine, followed by N-alkylation, to afford 5-methoxy-N-propy l-N-2'-propynyl-2-aminotetralin, (7) under bar. Reduction of (7) under bar with tributyltin hydride gave the tri-n-butyl tin derivative, (8) under bar, which was converted to (9) under bar by an iododemetalatio n reaction. Demethylation of (9) under bar gave the desired compound, (R,S)trans-5-OH-PIPAT, (3) under bar. The resolved (R) and (S)trans-5- OH-PIPAT, (3) under bar, were also quantitatively prepared. In vitro b inding studies showed the stereoselectivity of this new compound for b inding to dopamine D2-like receptors. S(-)-(3) under bar displayed hig h binding affinity, with inhibition constants (K-i) of 0.38, 0.09 and 0.67 nM for dopamine D2H (expressed in HEK293 cells), D3 (expressed in Sf9 cells) and D4H receptors (expressed in CHO cells), respectively. Using the same binding assays, the less active R(+) isomer displayed K -i values of 7.29, 4.87 and 16.44 nM for D2H, D3 and D4H receptors, re spectively. In addition, radiolabeling was successfully performed, eit her with the racemic tin derivative, (R,S)-<(11)under bar>, or using t he optically resolved tin derivatives R(+)- or S(-)-<(11)under bar>, t o give the final radiolabeled product, [I-125]R(+) or S(-)-(3) under b ar.