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

Zhi‐Ping ‐P Zhuang, Mei‐Ping ‐P Kung, William Clarke, Saul Maayani, Mu Mu, Hank F. Kung

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

(R,S)‐trans‐8‐Hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin 7, a new radioiodinated ligand based on 8‐OH‐DPAT, was reported as a potential ligand for 5‐HT1A receptors. The optically active (+)‐(R)‐ and (−)‐(S)‐7 were prepared to investigate the stereoselectivity of (R,S)‐7. Racemic intermediate 8‐methoxy‐2‐N‐n‐propyltetralin was reacted with the acyl chloride of (−)‐(R)‐O‐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 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 adenylyl cyclase activity in hippocampal membranes (Emax and EC50 were 24.5% and 5.4 nM, respectively), while (−)‐(S)‐7 showed no effect at 1 μM. The radioiodinated (+)‐(R)‐ and (−)‐(S)‐[125I]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP‐1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)‐(R)‐[125I]7, displayed high binding affinity to 5‐HT1A receptors (Kd = 0.09 ± 0.02 nM). In contrast, the (−)‐(S)‐7 isomer displayed a significantly lower affinity to the 5‐HT1A receptor (Kd > 10 nM). Thus, (+)‐(R)‐[125I]trans‐8‐OH‐PIPAT, (+)‐(R)‐7, an iodinated stereoselective 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. © 1995 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)452-458
Number of pages7
JournalChirality
Volume7
Issue number6
DOIs
StatePublished - 1995
Externally publishedYes

Keywords

  • 8‐OH‐DPAT
  • HPLC
  • I
  • diastereoisomer
  • optical column
  • radioligands
  • serotonin receptor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Catalysis
  • Pharmacology
  • Drug Discovery
  • Spectroscopy
  • Organic Chemistry

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