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Synthesis of (+)‐(R)‐ and (−)‐(S)‐ trans ‐8‐hydroxy‐2‐[ N ‐ n ‐propyl‐ N ‐(3′‐iodo‐2′‐propenyl)] aminotetralin: New 5‐HT 1A receptor ligands
Author(s) -
Zhuang ZhiPing,
Kung MeiPing,
Clarke William,
Maayani Saul,
Mu Mu,
Kung Hank F.
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070611
Subject(s) - chemistry , propenyl , stereochemistry , medicinal chemistry
(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‐HT 1A 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‐HT 1A 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 max and EC 50 were 24.5% and 5.4 n M , respectively), while (−)‐(S)‐ 7 showed no effect at 1 μ M. The radioiodinated (+)‐(R)‐ and (−)‐(S)‐[ 125 I] 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)‐[ 125 I] 7 , displayed high binding affinity to 5‐HT 1A receptors ( K d = 0.09 ± 0.02 n M ). In contrast, the (−)‐(S)‐ 7 isomer displayed a significantly lower affinity to the 5‐HT 1A receptor ( K d > 10 n M ). Thus, (+)‐(R)‐[ 125 I] trans ‐8‐OH‐PIPAT, (+)‐(R)‐ 7 , an iodinated stereoselective 5‐HT 1A receptor agonist, is potentially useful for study of in vivo and in vitro function and pharmacology of 5‐HT 1A receptors in the central nervous system. © 1995 Wiley‐Liss, Inc.