Synthesis of (+)-(R)- and (−)-(S)-trans-8-hydroxy-2-[N-n-propyl-N-(3′-iodo-2′-propenyl)] aminotetralin: New 5-HT1A receptor ligands

✍ Scribed by Zhi-Ping Zhuang; Mei-Ping Kung; William Clarke; Saul Maayani; Mu Mu; Hank F. Kung

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 690 KB
• Volume: 7
• Category: Article
• ISSN: 0899-0042
• DOI: 10.1002/chir.530070611

✦ Synopsis

R, S)trans-8-Hydroxy-2-[N-n-propy1-N-(3'-iodo-2'-propeny1)amino]tetraralin 7, a new radioiodinated ligand based on 8-OH-DPAT, was reported as a potential ligand for 5-HTlA receptors. The optically active (+)-(R)-and (-)-(S)-7 were prepared to investigate the stereoselectivity of (R, 3-7. Racemic intermediate 8-methoxy-2-N-n-propyltetralin was reacted with the acyl chloride of (-)-(R)-0-methylmandelic acid to form a mixture of (S,R)and (R, R)-diastereoisomers, which were separated by flash column chromatography. After removing the N-acyl group from the diastereoisomers, the desired (+)-(R)or (-)-(S)-7 was obtained by adding an N-iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for ~-HT,A receptors. (+ )-(R)-7 isomer displayed 100-fold higher affinity than the (-)-(S)-7 isomer. Biochemical study indicated that (+)-(R)-7 potently inhibited forskolin-stimulated adenylyl cyclase activity in hippocampal membranes (E, and ECm were 24.5% and 5.4 nM, respectively), while (-)-(S)-7 showed no effect at 1 p M . The radioiodinated (+)-(R)-and (-)-(S)-[125117 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP-1, acetonitrile/pH 7.0 buffer, 80120). The active isomer, (+)-(R)-[1251]7, displayed high binding affinity to ~-HT,A receptors (Kd = 0.09 k 0.02 nM). In contrast, the (-)-(S)-7 isomer displayed a sigdicantly lower affinity to the 5-HTIA receptor (Kd > 10 nM). Thus, (+)-(R)-[1251]trans-8-OH-PIPAT, (+)-(R)-7, an iodinated stereoselective 5-HT1, receptor agonist, is potentially useful for study of in Vivo and in vitro function and pharmacology of 5-HTlA receptors in the central nervous system.