SYNTHESIS OF -[N-N-PROPYL-N-(3'-IODO-2'-PROPENYL)]AMINOTETRALIN AND -[N-N-PROPYL-N-(3'-IODO-2'-PROPENYL)]AMINOTETRALIN - NEW 5-HT1A RECEPTOR LIGANDS())

-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin 7, a new radioiodin ated ligand based on 8-OH-DPAT, was reported as a potential ligand for 5-HT1A receptors. The optically active (+)-(R)- and (-)-(S)-7 were pr epared to investigate the stereoselectivity of (R,S)-7. Racemic interm ediate 8-methoxy-2-N-n-propyltetralin was reacted with the acyl chlori de of (-)-(R)-O-methylmandelic acid to form a mixture of (S,R)-and (R, R)-diastereoisomers, which were separated by flash column chromatograp hy. After removing the N-acyl group from the diastereoisomers, the des ired (+)-(R)- or (-)-(S)-7 was obtained by adding an N-iodopropenyl gr oup. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5-HT1A receptors. (+)-(R)-7 isomer displayed 100-fold higher affinity than the (-)-(S)-7 isomer. Biochemical study indicated that (+)-(R)-7 potently inhibited forskolin-stimulated adeny lyl cyclase activity in hippocampal membranes (E(max) and EC(50) were 24.5% and 5.4 nM, respectively), while (-)-(S)-7 showed no effect at 1 mu M. The radioiodinated (+)-(R)- and (-)-(S)-[I-125]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse ph ase column PRP-1, acetonitrile/pH 7.0 buffer, 80/20). The active isome r, (+)-(R)-[I-125]7, displayed high binding affinity to 5-HT1A recepto rs (K-d = 0.09 +/- 0.02 nM). In contrast, the (-)-(S)-7 isomer display ed a significantly lower affinity to the 5-HT1A receptor (K-d>10 nM). Thus, (+)-(R)-[I-125] trans-8-OH-PIPAT, (+)-(R)-7, an iodinated stereo selective 5-HT1A receptor agonist, is potentially useful for study of in vivo and in vitro function and pharmacology of 5-HT1A receptors in the central nervous system. (C) 1995 Wiley-Liss, Inc.